The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: ‘Talented’ Taxa from the Amaryllidaceae

Dr Sanjib Bhakta

Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates....

molecules Review The Phytochemistry and Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: ‘Talented’ Taxa from the Amaryllidaceae Cynthia Amaning Danquah 1, * , Prince Amankwah Baffour Minkah 1,2 , Theresa A. Agana 3 , Phanankosi Moyo 4 , Michael Ofori 1,5 , Peace Doe 6 , Sibusiso Rali 4 , Isaiah Osei Duah Junior 7 , Kofi Bonsu Amankwah 8 , Samuel Owusu Somuah 9 , Isaac Newton Nugbemado 1 , Vinesh J. Maharaj 4 , Sanjib Bhakta 10 and Simon Gibbons 11 1 2 3 4 5 6 Citation: Danquah, C.A.; Minkah, P.A.B.; Agana, T.A.; Moyo, P.; Ofori, M.; Doe, P.; Rali, S.; Osei Duah Junior, 7 8 I.; Amankwah, K.B.; Somuah, S.O.; et al. The Phytochemistry and 9 Pharmacology of Tulbaghia, Allium, Crinum and Cyrtanthus: ‘Talented’ 10 Taxa from the Amaryllidaceae. Molecules 2022, 27, 4475. https:// 11 doi.org/10.3390/molecules27144475 * Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, PMB, Kumasi, Ghana; p.minkah@kccr.de (P.A.B.M.); michof2825@gmail.com (M.O.); nugbemadokorbla@gmail.com (I.N.N.) Global Health and Infectious Disease Research Group, Kumasi Centre for Collaborative Research in Tropical Medicine, College of Health Sciences, Kwame Nkrumah University of Science and Technology, PMB, Kumasi, Ghana Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology, PMB, Kumasi, Ghana; tessyagana4christ@gmail.com Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa; u13386842@tuks.co.za (P.M.); u21749745@tuks.co.za (S.R.); vinesh.maharaj@up.ac.za (V.J.M.) Department of Pharmaceutical Sciences, Dr. Hilla Limann Technical University, Wa P.O. Box 553, Ghana Department of Pharmaceutical Sciences, School of Pharmacy, Central University, Accra, Ghana; pdoe@central.edu.gh Department of Optometry and Visual Science, College of Science, Kwame Nkrumah University of Science and Technology, PMB, Kumasi, Ghana; oseiduahisaiah@gmail.com Department of Biomedical Sciences, University of Cape Coast, Cape Coast, Ghana; kamankwah@stu.ucc.edu.gh Department of Pharmacy Practice, School of Pharmacy, University of Health and Allied Sciences, Ho, Ghana; sosomuah@uhas.edu.gh Department of Biological Sciences, Institute of Structural and Molecular Biology, Birkbeck, University of London, Malet Street, London WC1E 7HX, UK; s.bhakta@bbk.ac.uk The Centre for Natural Products Discovery (CNPD), Liverpool John Moores University, Liverpool L3 3AF, UK; s.gibbons@ljmu.ac.uk Correspondence: cadanquah.pharm@knust.edu.gh; Tel.: +233-265458216 Academic Editors: Agnieszka Ludwiczuk and Yoshinori Asakawa Received: 16 May 2022 Accepted: 28 June 2022 Published: 13 July 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and Abstract: Amaryllidaceae is a significant source of bioactive phytochemicals with a strong propensity to develop new drugs. The genera Allium, Tulbaghia, Cyrtanthus and Crinum biosynthesize novel alkaloids and other phytochemicals with traditional and pharmacological uses. Amaryllidaceae biomolecules exhibit multiple pharmacological activities such as antioxidant, antimicrobial, and immunomodulatory effects. Traditionally, natural products from Amaryllidaceae are utilized to treat non-communicable and infectious human diseases. Galanthamine, a drug from this family, is clinically relevant in treating the neurocognitive disorder, Alzheimer’s disease, which underscores the importance of the Amaryllidaceae alkaloids. Although Amaryllidaceae provide a plethora of biologically active compounds, there is tardiness in their development into clinically pliable medicines. Other genera, including Cyrtanthus and Tulbaghia, have received little attention as potential sources of promising drug candidates. Given the reciprocal relationship of the increasing burden of human diseases and limited availability of medicinal therapies, more rapid drug discovery and development are desirable. To expedite clinically relevant drug development, we present here evidence on bioactive compounds from the genera Allium, Tulgbaghia, Cyrtanthus and Crinum and describe their traditional and pharmacological applications. conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Molecules 2022, 27, 4475. https://doi.org/10.3390/molecules27144475 https://www.mdpi.com/journal/molecules Molecules 2022, 27, 4475 2 of 48 Keywords: Amaryllidaceae; alkaloids; Allium; Crinum; Tulbaghia; Cyrtanthus; phytochemicals; natural products; pharmacological activity; drug discovery 1. Introduction Amaryllidaceae belongs to the order Asparagales and consists of bulbous flowering plants separated into three infrageneric ranks: Agapanthoideae, Allioideae and Amaryllidoideae, as delineated by the Angiosperm Phylogeny Group [1]. The term “Amaryllidaceae” is frequently used in either phytochemical or pharmacological literature to refer to plants or alkaloids originating from the subfamily Amaryllidoideae [2,3]. Monocotyledonous plants constitute seventy-nine genera (including Allium, Crinum, Cyrtanthus, and Tulbaghia) with over 1000 species [4]. Aside from their broad pantropical distribution, Amaryllidaceae are located in Africa, the Mediterranean Coast and South America, and have high adaptation and speciation [5]. The genus Allium is distributed in temperate, arid, semi-arid and subtropical areas such as the Mediterranean region, central Asia, Africa and parts of Europe. As herbaceous geophyte perennials, Allium comprises a plethora of species with pungent linear leaves that may or may not arise from a bulb or rhizome [6,7]. The Tulbaghia genus, popularly called “sweet garlic”, “wild garlic”, or “pink agapanthus”, is crown shaped with outgrowth or appendages of the perianth and predominantly colonizes the Eastern cape belt of South Africa, and is adapted for growth in areas such as Europe and America [8,9]. The genus Crinum encompasses 104 species and appear as showy flowers on leafless stems, which thrive in the tropics and warm temperate parts, specifically Asia, Africa, America, and Australia [10]. Cyrtanthus is popularly known as “fire lily” due to its unique rapidly flowering response to natural bush fires. Most species are found in South Africa and play an important role in South African traditional medicine [11]. Amaryllidaceous plants are known for their ornamental, nutritional, and medicinal value. Given their attractive flowering plant-like features, Crinum species are prized for their umbel lily-like blossoms in China and Japan [3]. Concurrently, Amaryllidaceae are known for their longstanding exploitation in medicinal therapy owing to their inherent biosynthesis of chemically diverse bioactive compounds with peculiar biological properties. The use of proximate and mineral composition analysis enabled the identification of phytoconstituents [10,12], while in vitro, in vivo, and in silico model systems have permitted the unravelling of intrinsic pharmacological activities of the natural products and other alkaloids isolated from this source [13–15]. Of note, bioactive compounds from Amaryllidaceae possesses a wide range of bioactivities ranging from antioxidant [16,17], anti-inflammatory [16,18], antimicrobial [17], antifungal [19], antiviral [20,21], antiplasmodial [22–24], anticarcinogenic [18,25,26], antispasmodic [1,27], antiplatelet [28], antiasthmatic [29], antithrombotic [30,31], antitumor [25], antihyperlipidemic [25], antihyperglycemic [25,32,33], antiarthritic [25], antimutagenic [16], immunomodulatory [16] and several others [34]. Given the aforementioned biological activities, Allium, Tulbaghia, Cyrtanthus and Crinum are utilized in traditional medicinal therapy for varying diseases and conditions [35–41]. For example, Allium is used as concoctions, decoctions, extracts, and herbal preparations to treat angina, amoebic dysentery, arthritis, cardiovascular diseases, cholera, catarrh, dysmenorrhea, fever, headaches, hepatitis, stomach disorders, throat infections, and prostatic hypertrophy [30,31,35–38]. The genus Tulbaghia has unique pharmacotherapeutic properties and is utilized to manage ailments such as earache, pyrexia, tuberculosis, and rheumatism [9,42]. Crinum species are used to treat haemorrhoids, malaria, osteoarthritis, varicosities, wounds, urinary tract infections, and gynaecological remedies [40,41]. Cyrtanthus are also employed in the management of ailments associated with pregnancy, as well as cystitis, age-related dementia, leprosy, scrofula, headaches, chronic coughs, among others [43,44]. In modern clinical practice, galanthamine from Amaryllidaceae is a primary choice of drug in managing symptomatic neurological disorders such as Alzheimer’s Molecules 2022, 27, 4475 3 of 48 disease due to its selective inhibitory action on the acetylcholine biosynthetic enzyme, acetylcholinesterase [45]. The pancratistatin phenanthridone class of alkaloids are also promising chemotherapeutic drug candidates with unique cell line-specific antiproliferative properties, conferring a selective advantage for clinical development [46]. Although Amaryllidaceae represents a source of valuable bioactive compounds, developing promising drug candidates into clinically relevant therapeutics has been slow. Similarly, other genera in this family, including Cyrtanthus, Crinum and Tulbaghia, are untapped reservoirs and could serve as an alternative window for novel drug targets and warrant further investigation. This review consolidates evidence on the bioactive compounds from Allium, Tulbaghia, Crinum and Cyrtanthus and ascertains their traditional and pharmacological applications. Specifically, bibliographic searches were conducted on multiple standard databases (such as, Scopus, Web of Science, MEDLINE, Sci verse, Embase, Google scholar among others) using MESH and non-MESH terms to retrieve and synthesize relevant publications over the 3-month search period. This review highlights panoply of promising biomolecules from the taxa Amaryllidaceae and their prominent medicinal values. The evidence from this study could hasten drug discovery among the pharmaceutical industries. An update on the natural products from these lesser explored genera could also augment the lean pipeline of novel therapeutics. 2. The Genus Tulbaghia 2.1. Botanical Description Tulbaghia is made up of monocotyledonous species with herbaceous perennial bulbs covered by brown scales and are mostly found in Africa [8]. South African species possess bulb-like corms or rhizomes which are swollen, irregularly shaped and wrapped in dry, fibrous leaves [8]. Members of this genus usually possess a raised crown-like structure or ring at the center of their flower tube [8]. Their seeds are black, flat and elongated with the mature ones having embryos [8]. Examples of species of this genus are Tulbaghia violacea (T. violacea), Tulbaghia acutiloba Harv. (T. acutiloba), Tulbaghia capensis L. (T. capensis) and Tulbaghia cepacea L.f (T. cepacea) [8]. 2.2. Geographical Distribution and Traditional Uses of Tulbaghia Species With approximately 66 species (https://www.kew.org/science accessed on 22 February 2022) [47], Tulbaghia is the second-most species-rich genus within Amaryllidaceae. Tulbaghia is a monocotyledonous genus comprised morphologically of herbaceous perennial bulbous species, which produce a variety of volatile sulfur compounds, hence resulting in a distinct pungent garlic odor released by bruised plants [8,48]. The genus was named by Carl Linnaeus after Ryk Tulbagh (1699–1771), a former governor of the Cape of Good Hope in South Africa, where most of the native species are to be found, particularly in the Eastern Cape Province [49]. In addition to South Africa, the genus is widely distributed across southern African countries including Botswana, Lesotho, Swaziland, and Zimbabwe, where the plant is revered in folk medicine being used for the treatment of a plethora of infectious and non-infectious diseases [9] as highlighted in Table 1. Table 1. Geographical distribution and traditional uses of Tulbaghia species. Plant Species Geographical Distribution T. violacea Indigenous to the Eastern Cape, KwaZulu-Natal, Gauteng, Free State and Mpumalanga Provinces of South Africa. T. alliacea Native to South Africa and grows mostly in the Eastern Cape and southern KwaZulu-Natal Provinces of South Africa. Traditional Uses The leaves and bulbs are used in the management of fever and colds, tuberculosis, asthma, and stomach problems. The leaves are eaten as vegetables and for the management of oesophageal cancer. It is also used as a snake repellent. Its bruised rhizome is used locally in bathwater to relieve fever, rheumatism, and paralysis, and in small doses as a laxative. T. alliacea is used for the management of stomach problems, asthma, and pulmonary tuberculosis. Its rhizome infusion is administered as an enema. References [8,50] [8,51] Molecules 2022, 27, 4475 4 of 48 Table 1. Cont. Plant Species Geographical Distribution Traditional Uses References T. simmleri Native to the South African Drakensberg mountains growing as isolated plants on rocky ledges. Bulbs and leaves are used as a remedy for gastrointestinal ailments, enemas, high blood pressure, heart problems, chest complaints, high cholesterol, constipation, rheumatism, asthma, fever, pulmonary tuberculosis, earache, human immunodeficiency virus (HIV), paralysis, and cardiovascular diseases. [50,52] T. acutiloba leaves are used as a culinary herb and snake repellent. It is used to treat barrenness, flu, bad breath, and as an aphrodisiac. It is also cultivated to keep snakes away from the homestead. [8] It is used as a culinary herb and snake repellent. [53] It is used for ornamental purposes. [8] Its rhizome is scraped clean and boiled in stews or roasted as a vegetable. Its leaves and stems are used as a culinary herb and protective charm. [53] It is traditionally used as a love charm. [53] T. acutiloba T. natalensis T. cernua T. leucantha T. ludwigiana Found in the rainfall regions of southern Africa, occurring in the Eastern Cape, KwaZulu-Natal, Limpopo, Free State, Gauteng, North West, and Mpumalanga Provinces of South Africa, as well as in Lesotho, Swaziland and Botswana. Although native to South Africa, but is now grown worldwide. Commonly found in the Eastern Cape, Free State, Gauteng, KwaZulu-Natal, Limpopo, Mpumalanga, North West and Western Cape Provinces of South Africa. Widely distributed in southern Africa including Botswana, Lesotho, South Africa, Swaziland, Zambia, and Zimbabwe. Commonly found in the Eastern Cape, KwaZulu-Natal, Northern Provinces of South Africa and in Swaziland. 2.3. Phytochemistry of Tulbaghia Tulbaghia produces many different classes of compounds with diverse chemical structures dominated by sulfur-containing natural products (Figure 1; Table S1). Figure 1. Chemical space of compounds identified from T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. PCA analysis carried out using DataWarrior [54]. Most compounds reported have a small molecular weight (<500) and are of a broad lipophilicity (Figure 2). Molecules 2022, 27, 4475 5 of 48 Figure 2. Analysis of cLogP and molecular weight space occupied by compounds identified in T. violacea. Blue circles are sulfur-containing compounds while red circles are compounds devoid of sulfur in their chemical structures. Plot generated using DataWarrior [54]. Tulbaghia violacea has been the most widely investigated for its phytochemistry and pharmacological properties. To date, close to 100 compounds have been tentatively identified, largely using gas chromatography techniques, from different parts of this species (Supplementary File S1) [55]. Most prominent are the sulfur compounds with reported broad-spectrum pharmacological activity. The thiosulfinate marasmicin (1) is the most prolific antimicrobial compound reported thus far from this genus [56]. This compound is formed from its precursor compound marasmin (2), by the enzyme c-lyase. Marasmicin is responsible for the characteristic garlic odor generated by damaged plants [48]. Other notable compounds produced by this species include phenols, tannins and flavonoids [55], which are also responsible for several observed biological activities. Phytochemical characterization has been carried out, albeit minimally for other Tulbaghia species particularly T. alliacea and T. acutiloba. Unlike other genera in Amaryllidaceae, Tulbaghia is so far devoid of any alkaloids [57,58]. Despite the extensive in vitro pharmacological screening of extracts of Tulbaghia, it is possible that less effort has been made to isolate and identify their active principles. Hence, the phytochemistry of the genus Tulbaghia largely remains understudied. The chemicals structurers of noteworthy compounds isolated from T. violacea have been represented in Figure 3. 2.4. Pharmacological Studies of Tulbaghia Species Because of its perceived medicinal value, Tulbaghia has received marked interest within the scientific community which has meticulously subjected it to various in vitro and in vivo studies experimentally evaluating its pharmacological activities. The volume of published studies generated from these investigations mirror the distribution of the genus with most articles on Tulbaghia having emerged from South Africa (Table 2), a country highly rich in this genus both in terms of species diversity and abundance. Molecules 2022, 27, 4475 6 of 48 Figure 3. Chemical structures of compounds identified in T. violacea. (1) Marasmicin (1), (2) β → marasmin (2), allicin (3)—possesses antibacterial and antifungal activity, D-fructofuranosyl-β(2→6)α β → α α methyl-α-D-glucopyranoside (4), β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside (5), methyl-αD -glucopyranoside (6), bis(methylthiomethyl) disulfide (7)—found to constitute 48% of volatiles in aerial parts of T. violacea [55], methyl-2-thioethyl thiomethyl trisulfide (8)—found to constitute 16% of volatile compounds in aerial parts of T. violacea [55], methyl (methylthio)methyl disulfide (9)—found to constitute 10 % of volatile compounds in aerial parts of T. violacea [55], naphthalene (10)—interestingly observed to significantly increase in concentration in plants infected by the fungus Beauveria bassiana in comparison to untreated controls [59], nonanal (11)—also observed to significantly decrease in concentration in plants infected by the fungi Beauveria bassiana in comparison to untreated controls [59] and finally kaempferol (12)—which possesses multiple biological activities including antioxidant, anticancer and anti-inflammatory properties [60–62]. Table 2. Published documents on the genus Tulbaghia per country. Country No. of Documents * South Africa United Kingdom United States Czech Republic Italy India 99 15 12 8 7 6 Molecules 2022, 27, 4475 7 of 48 Table 2. Cont. Country No. of Documents * Germany Australia China Belgium 5 3 3 2 * Data retrieved following query of the Scopus database (https://www.scopus.com/, accessed on 22 February 2022) using the keyword “Tulbaghia”. The search was carried out on 22 February 2022. The greatest numbers of pharmacological screens have been on interrogating the antimicrobial properties of this genus. This is closely followed by cardiovascular, antioxidants and cancer investigations as shown in Table 3. T. violacea prominently features, being the most studied species, with T. alliacea and T. aticulata having received minimal attention. Table 3. Number of published studies per specific disease or pharmacological area. Disease No. of Published Studies # Antimicrobial Cancer Antioxidant Diabetes Cardiovascular Antithrombogenic Miscellaneous 26 11 13 2 12 2 17 # Studies considered are those published from 1997 to 2022. A number of these, published before 2013, have been succinctly discussed by Aremu and Van Staden [8]. 2.4.1. Antimicrobial and Antiparasitic Activity As antimicrobial resistance continues to be a global health threat, the need to find therapeutic alternatives has never been more urgent [63]. This has encouraged scientists to search for novel alternatives with natural products having drawn marked interest as a potential oasis of new antimicrobial agents [64–66]. Tulbaghia has received significant relevance in this regard, with multiple studies providing ample evidence substantiating its use as an antimicrobial agent. Extracts of T. violacea have potency against many microbial species including those designated as priority by the World Health Organization. These include Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus) and Klebsiella pneumoniae (K. pneumoniae) with MIC values ranging between 20 and 300 µg/mL [67]. This activity was confirmed in another study where the disc diffusion method was used [68]. In addition to bacteriostatic activity, extracts of T. violacea have shown noteworthy potency against yeasts including Candida albicans (C. albicans) and Candida parapsilosis (C. parapsilosis) with MIC and MMC values ranging between 20 and 40 µg/mL [68]. Beyond human pathogens, extracts of T. violacea have activity against microorganisms of agricultural significance, for example against the fungus Aspergillus flavus (A. flavus), which is responsible for significant agricultural produce loss at a global scale due to production of aflatoxins [69]. Extracts of T. violacea compromised cell wall synthesis by significantly reducing β-glucan and chitin synthesis in A. flavus corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively [70]. Further studies suggested an alternative mode of action (MoA) via reduction of ergosterol production in fungi [71]. Interestingly, related to value in agriculture, a patent has been filed on the use of extracts of T. violacea as a plant protecting remedy as a substitute for chemical agents [72]. Some thought-provoking studies have shown that growth conditions including light intensities, watering frequency and pH, substantially impact both growth and biological potency of T. violacea extracts against Fusarium oxysporum (F. oxysporum) [73,74]. Likewise, storage conditions of dried plant material also affect the antimicrobial potency of extracts [56]. In addition to antimicrobial activity, T. violacea has shown good antiparasitic activity against the parasitic worm Meloidogyne incognita (M. incognita) on tomato roots and in soil [75]. Antiparasitic activity has also Molecules 2022, 27, 4475 8 of 48 been observed against Trypanosoma brucei (T. brucei) (IC50 = 2.83 µg/mL) and Leishmania tarentolae (L. tarentolae) (IC50 = 6.29 µg/mL) [67]. Table 4 highlights the antimicrobial activity of Tulbaghia species. Table 4. Antimicrobial activity of Tulbaghia species. Plant Species Extraction Solvent Plant Part Used T. violacea Dichloromethane Bulbs T. violacea Hexane and ethanol Flowers and callus cultures T. violacea Water Bulbs T. violacea Acetone Bulbs T. violacea Water Roots, bulbs, leaves and flowers T. violacea Dichloromethane Bulbs Biological Activity MIC ranging from 20 to 300 µg/mL against Bacillus subtilis, methicillin-resistant S. aureus, S. epidermidis, E. coli, K. pneumoniae, P. aeruginosa, C. albicans and C. parapsilosis. Moderate to strong broad-antimicrobial (E. coli, P. aeruginosa, S. aureus, Aspergillus niger and C. albicans) activity observed by zone of inhibition in the agar well disc diffusion method. Significant reduction in A. flavus β-glucan and chitin synthesis corresponding to a dose-dependent inhibition of the enzymes β-glucan and chitin synthase, respectively.This results in inhibition of ergosterol production in the fungus. Varied light intensities, pH and watering frequencies substantially impacted both growth and potency of plant extracts against the fungi F. oxysporum. Significantly compromised population densities of the nematode M. incognita race 2 on tomato roots and in the soil. Antiparasitic activity against T. brucei (IC50 = 2.83 µg/mL) and L. tarentolae (IC50 = 6.29 µg/mL). References [67] [68] [70,71] [73,74] [75] [67] 2.4.2. Anticancer Activity Owing to the need for novel anticancer agents [76] and motivated by the success of cancer drug discovery projects from natural products [77], Mthembu and Motadi in (2014), evaluated the in vitro anticancer properties of crude methanol extracts of T. violacea using an MTT assay [78]. Extracts displayed time- and concentration-dependent antiproliferative properties against cervical cancer cell lines with an IC50 of 150 µg/mL. The MoA was deciphered to be induction of apoptosis by a p53-independent pathway [78]. However, in contrast to this finding, continued work showed a proportional increase in the activity of caspase 3/7, and the expression of p53 genes strongly suggests apoptosis was triggered by a p53-dependent pathway [79]. This latter finding has been partly substantiated by data emerging from a study examining the antineoplastic properties of T. violacea against ovarian tumor cells. These extracts were shown to partially induce both apoptosis and necrosis with the most pronounced activity due to induction of autophagy [80]. Triple-negative breast cancer remains one of the most challenging cancers, being highly aggressive [81]. T. violacea extracts have demonstrated good cytotoxic activity against MDAMB-231, with an IC50 of 300 µg/mL [82]. Additionally, extracts inhibited migration of the cancer cell lines (metastasis), an important physiological process in the progression of this cancer [83]. In addition to the gynecological cancers, antineoplastic properties of T. violacea were further observed against pancreatic cancer with 63% inhibition of cell proliferation at a concentration of 250 µg/mL [68]. Against a non-sex-specific cancer, T. violacea showed noticeable activity against oral cancer with an IC50 of 0.2 and 1 mg/mL for acetone and water-soluble extracts, respectively. Extracts activated caspase activity in a dose-dependent manner leading to induction of apoptosis in the human oral cancer cell line [84]. Using a bioassay guided approach, the active anticancer compounds in T. violacea have been identified to be glucopyranosides D-fructofuranosyl-β (2→6)-methyl-α-D-glucopyranoside and β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside. Both compounds act by mediating induction of apoptosis in Chinese hamster cells by targeting the mitochondrial (intrinsic) pathway [85,86]. A summary of the anticancer activity of Tulbaghia species is shown in Table 5. Molecules 2022, 27, 4475 9 of 48 Table 5. Anticancer activity of Tulbaghia. Plant Species Extraction Solvent Plant Part Used T. violacea Methanol Leaves and roots T. violacea Methanol, butanol, and hexane Leaves T. violacea Methanol:water:formic acid (80:20:0.1, v/v/v) Flowers T. violacea Water and methanol Leaves T. violacea Hexane and ethanol Flowers and callus cultures T. violacea Acetone and water Leaves T. violacea Methanol:water (1:1) Whole plants T. violacea Water Whole plants Biological Activity Marked time- and dose-dependent cytotoxic effect on cancer cell lines. Induced apoptosis using p53-independent pathway. Methanol extract was prolific against multiple cell lines. Hela and ME-180 cell lines treated with methanol and hexane extracts showed an increase in caspase 3/7 activity. Both methanol and hexane extracts induced a 10-fold increase in expression of p53 gene in Hela cells. Demonstrated activity against ovarian tumor cells. Water-soluble extract emerged as the most cytotoxic (IC50 = 314 µg/mL), compared to the methanol extract (IC50 = 780 µg/mL), against the MDA-MB-231 triple-negative breast cancer cell line. Water-soluble extract prevented cell migration completely for 13 h at 300 µg/mL. Extracts showed marked cytotoxicity (60–74% growth inhibition at 250 µg/mL) against three different cell lines (Hep G2, PC-3 and MCF-7). Anticancer activity against oral cancer with an IC50 (acetone extract) of 0.2 mg/mL; IC50 (water extract) of 1 mg/mL. Two pro-apoptotic glucopyranosides D-fructofuranosyl-β (2→6)-methyl-α-D-glucopyranoside and β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside isolated and identified as active anticancer agents in the plant. MoA of the three compounds, namely methyl-α-D-glucopyranoside, D-fructofuranosyl-β (2→6)-methyl-α-D-glucopyranoside and β-D-fructofuranosyl-(2→6)-α-D-glucopyranoside isolated from the water extract, deciphered to be through induction of apoptosis by targeting the mitochondrial (intrinsic) pathway References [78] [79] [80] [82] [68] [84] [85] [86] 2.4.3. Antioxidant Activity The imbalance of reactive oxygen species (ROS) and antioxidants in the body can lead to oxidative stress [87]. This physiological condition can result in cellular and tissue damage [88]. Oxidative stress is associated with pathologies including cancer, cardiovascular disease, diabetes, and neurodegenerative diseases amongst others [88,89]. To avert the development of oxidative stress, attenuation of ROS has been identified as a viable target, with natural products seen as a potential source capable of neutralizing it [88]. Tulbaghia has generated some interest on this front particularly as it is rich in compounds with proven antioxidant activity including phenols, tannins and flavonoids. Multiple studies have demonstrated that extracts of Tulbaghia have marked antioxidant activity as assessed using different assays in vitro including Trolox equivalent antioxidant capacity (TEAC; also commonly referred to as the ABTS assay), ferric-reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) (Table 6) [58,80,90,91]. Furthermore, using an in vivo model of Caenorhabditis elegans, T. violacea extracts attenuated oxidative stress produced by a free radical generator, (2,2′ -azobis-2-amidinopropane dihydrochloride; AAPH), in the roundworm [80]. Data from these studies strongly suggested continued investigation of other species in the search for more potent antioxidant agents from Tulbaghia. The antioxidant activity of Tulbaghia species is highlighted in Table 6. Molecules 2022, 27, 4475 10 of 48 Table 6. Antioxidant activity of Tulbaghia species. Plant Species Extraction Solvent Plant Part Used T. violacea Water Leaves T. violacea Methanol/water/formic acid (80:20:0.1, v/v/v) T. acutiloba Hydro-methanolic extracts T. violacea Hexane and ethanol T. violacea T. acutiloba T. alliacea T. cernua T. leucantha T. ludwigiana T. natalensis Acetone Acetone Acetone Acetone Acetone Acetone Acetone Flowers Roots, rhizomes, leaves and flowers Flowers and callus cultures Leaves Leaves Leaves Leaves Leaves Leaves Leaves Biological Activity Dose-dependent antioxidant activity measured using the DPPH (Log IC50 = 0.49 mg/mL) and ABTS (Log IC50 = 0.24 mg/mL) assays Marked antioxidant activity was observed using 3 different types of assays, namely DPPH, FRAP and TREC Dose-dependent antioxidant activity observed with the rhizome extract emerging as the most active plant part (IC50 DPPH = 0.202 mg/mL and peak scavenging activity of 95) Dose-dependent antioxidant activity with IC50 ranging from 1.933 to 7.350 mg/mL in the DPPH assay IC50 DPPH = 0.08 mg/mL; IC50 ABTS = 0.03 mg/mL IC50 DPPH = 0.16 mg/mL; IC50 ABTS = 0.07 mg/mL IC50 DPPH = 0.06 mg/mL; IC50 ABTS = 0.06 mg/mL IC50 DPPH = 0.21 mg/mL; IC50 ABTS = 2.34 mg/mL IC50 DPPH = 0.39 mg/mL; IC50 ABTS = 0.03 mg/mL IC50 DPPH = 0.26 mg/mL; IC50 ABTS = 0.09 mg/mL IC50 DPPH = 2.70 mg/mL; IC50 ABTS = 0.04 mg/mL References [92] [80] [91] [68] [84] [84] [84] [84] [84] [84] [84] 2.4.4. Antidiabetic, Anticardiovascular and Antithrombogenic Activity The incidence of diabetes and cardiovascular diseases continues to grow substantially across the globe, with both conditions combined accounting for the highest global morbidity and mortality [93,94]. Both of these chronic conditions are closely linked with cardiovascular disease being responsible for high morbidity and mortality in diabetic patients [95]. Tulbaghia has been documented in ethnopharmacological studies for the treatment of these ailments with emerging scientific data strongly validating its use. In streptozotocin diabetes-induced rat models, T. violacea attenuated diabetes-associated physiological conditions resulting in improved body weights, reduced fasting blood glucose levels, enhanced glucose tolerance and significantly elevated plasma insulin and liver glycogen content [96]. These data were corroborated in another study in which T. violacea noticeably reduced blood glucose and serum lipid (triglyceride (TG), total cholesterol (TC), and very low-density lipoprotein (VLDL)) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model [97]. In an assessment for negating cardiovascular associated conditions, T. violacea in in vivo models markedly reduced systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP) and the heart rate in both ageinduced and spontaneous hypertensive rats [98]. Furthermore, dosing rats with extracts of T. violacea led to improved kidney function [99]. This is an essential pharmacological property as kidney function is impaired in hypertension leading to high morbidity and mortality in people suffering from cardiovascular diseases [100]. One of the multiple factors strongly associated with cardiovascular disease is atherothrombotic vascular disease (AVD). Platelet aggregation plays a role in development of AVD and subsequent cardiovascular events [90,101]. Against this background, platelet aggregation has been identified as a key process to target to prevent AVD. Encouragingly, T. violacea demonstrated marked potency being able to significantly inhibit platelet adhesion 15 min post-exposure (Table 7) [90,92]. Table 7. Antidiabetic, anticardiovascular and antithrombogenic activity of Tulbaghia species. Plant Species Extraction Solvent Plant Part Used T. violacea Methanol Rhizome T. violacea Methanol Rhizome Biological Activity References Diabetes Attenuated diabetes associated physiological complications in streptozotocin-induced diabetic rats. Noticeably reduced blood glucose and serum lipid (TG, TC, and VLDL) levels while raising plasma insulin in a streptozotocin-induced diabetic rat model. [96] [97] Molecules 2022, 27, 4475 11 of 48 Table 7. Cont. Plant Species Extraction Solvent Plant Part Used T. violacea Methanol Leaves T. violacea Methanol Rhizome T. acutiloba Hydro-methanolic extracts Roots, rhizomes, leaves and flowers T. violacea Water Leaves T. violacea Water Leaves Biological Activity References Cardiovascular Markedly reduced systolic BP, diastolic BP, mean arterial pressure and the heart rate in both age-induced and spontaneous hypertensive rats. 50 mg/kg significantly improved kidney function in vivo. All extracts inhibited the Angiotensin-1-Converting Enzyme in vitro (> 50 % inhibition at a concentration range of 125–1000 µg/mL). Extracts of leaves demonstrated activity comparable to that of the control drug ramipril. [98] [99] [91] Antithrombogenic Noticeable inhibition of platelet adhesion by a novel scaffold consisting of polycaprolactone incorporated with 10 % (w/w) plant extracts. Marked inhibition of platelet adhesion (70% inhibition at 0.1 mg/mL within 15 min post-exposure). [90] [92] 2.4.5. Miscellaneous Pharmacological Activity In addition to diabetes and cardiovascular diseases, T. violacea has shown activity against another chronic condition, Alzheimer’s disease. In an in vivo Alzheimer’s disease transgenic C. elegans strain model, T. violacea significantly reduced 1-42 β-amyloid peptide formation (Table 8) [80]. T. violacea exhibited in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA [102] and validating its traditional use for the treatment of epilepsy. T. violacea displayed marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5% w/v and 10% w/v) [59], further enhancing its credentials as a potential agricultural product. Somewhat concerning is that, extracts of T. violacea also induced genotoxic effects albeit at high test concentrations (250, 500 and 1000 µg/mL) in the Allium cepa assay [103]. Furthermore, broad murine macrophage antiproliferative and cytotoxicity activity, influenced by extract test concentrations, type of solvent and plant part used, have been observed (Table 8) [104]. There is consequently a need for rigorous assessment of safety of extracts of this and other species of the genus Tulbaghia. Table 8. Miscellaneous biological properties of extracts of Tulbaghia species. Plant Species Extraction Solvent T. violacea Methanol/water/formic acid (80:20:0.1, v/v/v) Plant Part Used Flowers T. violacea Methanol Leaves T. violacea Acetone Mixture of leaves and bulbs T. violacea Water Leaves, stems, and roots T. violacea Water and ethanol Leaves, stems, and roots Biological Activity Reduced 1-42 β-amyloid peptide formation and arrested oxidative stress in vivo. Demonstrated in vivo anticonvulsant activity by attenuating tonic convulsions induced by either pentylenetetrazole, bicuculline, picrotoxin, strychnine or NMDLA. Marked tick repellence properties of fungus-exposed plants at low treatment concentrations (5 % w/v and 10 % w/v). Induced conspicuous genotoxicity effects at high test concentrations (250, 500 and 1000 µg/mL) in the A. cepa assay. Broad murine macrophage antiproliferative and cytotoxicity activity influenced by both extract test concentrations, type of solvent and plant part used. References [80] [102] [59] [103] [104] 3. The Genus Allium 3.1. Botanical Description Species of the genus Allium are mostly found in warm–temperate and temperate zones of northern hemisphere as well as the boreal zone [105]. They are petaloid perennial herbs with parallel narrow leaves [33] and possess true bulbs, which are sometimes found on rhizomes [106]. Allium species are also characterized by onion or garlic odor and flavor similar to Tulbaghia [106]. Well known species include Allium cepa (A. cepa), Allium sativum Molecules 2022, 27, 4475 12 of 48 (A. sativum), Allium ascalonicum (A. ascalonicum,), Allium porrum (A. porrum), and Allium schoenoprasum (A. schoenoprasum) (chive) [33] Allium has over 500 species making it the largest genus of Amaryllidaceae [6,7]. There are plethora of species, notably A. cepa and A. sativum [107–109]. Other examples grown for their medicinal and nutraceutical value are Allium ducissae (A. ducissae), Allium strictum (A. strictum), Allium umbilicatum (A. umbilicatum), Allium victorialis (A. victorialis), A. ascalonicum, Allium chinense (A. chinense), Allium tuberosum (A. tuberosum), Allium griffithianum (A. griffithianum), Allium oreoprasum (A. oreoprasum), and Allium oschaninii (A. oschaninii). Species tolerate varying climatic conditions, hence are geographically distributed across several continents, including Asia, Africa, the Americas, and Europe [107,110]. Fernandes et al. identified A. cepa that colonizes four different geographical regions of the Madeira island, an archipelago near the North Atlantic ocean with a hot and/or warm-summer Mediterranean climate conditions [107]. As the world’s second-most relevant and cultivated horticulture vegetable crop, the onion (A. cepa), is distributed in over 175 countries and covers approximately six million hectares of the total land size of the world. Approximately two-thirds (66%) of global onion production emanates from the Asia, with China and India being the world’s largest producers [111]. The maximal diversification of A. cepa is found in Iran and Afghanistan’s Mediterranean basin. A. cepa thrives in areas with boreal, temperate, and tropical climates [108]. Similarly, A. sativum (garlic) bears close resemblance to onions and originates from Central Asia but has spread to include regions in Europe, America, and Africa [112]. The global garlic production estimates show that out of the 28.5 million tonnes (MT) of A. sativum cultivated, the majority (91.6%; 26.1 MT) were from Asia, followed by Europe (3.0%; 0.86 MT), America (2.9%; 0.83 MT), and with the least from Africa (2.7%; 0.73 MT) [112]. Bartolucci et al. identified A. ducissae, a new breed of Allium that grows in the mountainous regions of the Central Apennines in the Abruzzo and Lazio counties of Italy [113]. Furthermore, A. strictum, a Eurasian species, is distributed across China, Europe, Russia, Kazakhstan, Kyrgyzstan, and Mongolia [114,115]. A. umbilicatum, also called gladiolus or leek is usually localized in semi-arid regions and can tolerate sub-zero freezing winters [116]. It occurs as a weed in oases and span across Afghanistan, Iran, Pakistan, Turkmenistan, Tajikistan, and central and Eastern Asian regions [116]. As a representative circumboreal plant, A. victorialis has a wide altitudinal climatic tolerance [117]. It is predominantly located in lowland deciduous forest and subalpine birch forest, but seldom found in the subalpine meadows [117]. This species is scattered distribution on the island stretches of Japan, Russia, and Northern China [117,118]. Although practically grown throughout the world, A. ascalonicum, also called shallot, is native to the Middle East, and the name is derived from the Syrian city Ascalon. These shallots are distributed on the main islands of Indonesia, in Bangladesh, Japan, Korea, Malaysia, Taiwan, and Thailand [119]. A. chinense (locally referred to as Chinese/Japan onion or scallion, Kiangski scallion, oriental onion, Rakkyo) is an uncommon Allium species found mainly in the tropical and sub-tropical regions of China, Japan, Vietnam, and eastern areas of India [111,120]. A. tuberosum is an indigenous species native to southeastern Asia and regarded as a lateseasonal bloomer. During the initial growth phases, A. tuberosum is evergreen in hot climates but succumbs to cold climatic conditions. However, the Chinese chive becomes tolerant to all seasonal variations [121,122]. A. griffithianum and A. oreoprasum are geographically skewed towards the mountainous regions of Pakistan, Afghanistan, Kyrgyzstan, Uzbekistan, and Tajikistan [123], whereas A. oschaninii are located in the Darvaz mountains of Central Tajikistan [124]. 3.2. Traditional Uses of Genus Allium Increasing scientific evidence asserts the traditional uses of plants in folklore medicine [124–126]. Researchers over the years have investigated various parts of local medicinal plants to identify phytoconstituents with potential bioactivity, and further develop them into new drug therapies [127,128]. Allium species contain the common phytocompounds (anthocyanins, flavonoids, organosulfur, sterols, saponins, phe- Molecules 2022, 27, 4475 13 of 48 nolic acids, amino acids, vitamins and minerals) [129–132] with innumerable biological properties [130–133]. Owing to these biological advantages, Allium species are locally used in managing various diseases affecting human organs and organ systems such as inflammation, microbial pathologies and oxidative stress injuries [130–133]. In particular, A. cepa is used to treat alopecia, hearing impairment, menstrual disorders, erectile dysfunction and ocular and metabolic diseases [133–135]. Similarly, A. sativum is employed in the management of hematological disorders, carcinomas, muscle weakness and compromised airways [135–139]. Other varieties of Allium species also serve as appetizers, nerve soothers, and relieving agents against digestive, respiratory, and urinary system discomfort as seen in Table 9. Table 9. Traditional medicinal uses of Allium species. Plant Species Mode of Preparation A. cepa Raw, juice of bulb or rhizome, paste, decoctions, cataplasm, maceration, infusion A. sativum Extracts of leaves or bulb A. umbilicatum Raw or cooked bulb, leaves, flowers A. victoralis Fresh, pickled, boiled and salted flowers, leaves and roots A. ascalonicum/A. cepa var aggregatum Bulb and leaves A. chinense Flower, leaves, roots, seedpods A. tuberosum Raw or cooked leaves, roots, oils from seed A. griffithianum Leaves and bulb A. oreoprasum Leaves and bulb Traditional Medicinal Uses Alopecia, antilithic (stone disease), anti-obesity, blood purifying, bronchitis, constipation, cardiovascular disease, cough, diabetes, eye diseases, erectile dysfunction, fever, hearing loss, headaches, hemorrhoids, epilepsy, oligomenorrhea, jaundice, lower gastrointestinal bleeding, prostate cancer, rheumatism, rubefacient, sinusitis, stomach pains, snake bites, skin diseases, teeth disorders, reduce flatulence, wound healing Antiseptic, anthelmintic, antithrombotic, antilipidemic, aphrodisiac, anti-greying of hair, bronchitis, carminative, cough, colic, cancers (gastric, prostate, colorectal adenomatous polyps, squamous cell carcinoma), diabetes, diaphoretic, dysentery, eczema, facial paralysis, fever, flatulence, galactagogue, high blood pressure, intestinal worms, liver disorders, rheumatism, scabies, tetanus, stomach pains, tuberculosis Non-specific reduction in blood cholesterol levels, tonify digestive and circulatory systems Appetizer, amenorrhea, pediatric otitis, bronchitis, diarrhea, dropsy, expectorant, hypofunction of stomach, inflammatory eye diseases, meteorism, gastroenteritis, heart diseases (atherosclerosis), rheumatism Allergies, appetizer, cold, cancers, fever, obesity, rheumatoid arthritis, soothes nerves, diabetes, post-menopausal syndrome Angina pectoris, astringent, bronchitis, carminative, chest pains, diarrhea, expectorant, pleurisy, tenesmus in cases of dysentery, reducing cholesterol, tonic to the digestive and circulatory systems Asthma, abdominal pain, carminative, cuts and wounds, diabetes, diarrhea, kidney and bladder weakness, nocturnal emission, urinary incontinence, spermatorrhea, stomachic Carminative, colic indigestion, dyspepsia, diabetes control Cough and cold, diabetes control, diarrhea, dysentery, fever, gastritis, oedema, headache, jaundice, stomachache, rheumatism, numbness of limbs Reference [133–135] [135–139] [116] [140] [141–145] [146] [147] [124] 3.3. Phytochemistry of Allium Owing to the numerous traditional uses of these species, it is not surprising that the genus contains several phytoconstituents which may be responsible for their observed activity. Table 10 outlines various phytochemicals isolated, their geographic location and their biological activity. Molecules 2022, 27, 4475 14 of 48 Table 10. Bioactive compounds isolated from Allium species. Plant Species Plant Part Country A. ursinum L. Leaves, underground parts, fresh flowers Poland Bulgaria A. mongolicum Aerial parts China A. cepa. A. cepa L. Pigmented scales of red onion, bulbs, red onion skin waste Naples Isolated Compounds 1,2-di-O-α-linolenoyl-3-O-β-D-galactopyranosyl-snglycerol; β-sitosterol3-O-β-D-glucopyranoside; kaempferol 3-O-β-glucopyranoside and kaempferol 3-O-β-neohesperidoside. (-S-)-spirost-5-en-3β-ol tetrasaccharide, (25R)-spirost-5,25(27)-dien-3 β-ol tetrasaccharide, 3-hydroxypregna-5,16-dien-20-one glycoside. Thymidine, adenosine, astragalin (kaempferol-3-O-β-D-glucopyranoside, kaempferol-3-Oβ-D-glucopyranosyl-7-O-β-D-glucopyranoside, kaempferol-3-O-β-D-neohesperoside, and kaempferol-3-O-β-D-neohesperoside-7-O-β-D glucopyranoside. Mongoflavonoids A1 , A2 , A3 , A4 , B1 , B2 and monogophenosides A1 , A2 , A3 , B. Quercetin. 3-O-(3′′ -O-β-glucopyranosyl-6′′ -O-malonyl-βglucopyranoside)-4-O-β-glucopyranoside, cyanidin 3,4′ -di-O-β-glucopyranoside, cyanidin-4′ -O-β-glucoside, peonidin 3-O-(6′′ -O-malonyl-β-glucopyranoside). 5-hydroxy-3-methyl-4-propylsulfanyl-5H-furan-2-one, (hydroxymethyl) furfural, acetovanillone, methyl 4-hydroxyl cinnamate and ferulic acid methyl ester. 3-O-β-glucopyranoside and 3-O-(6′′ -O-malonyl-β-glucopyranoside) of 5-carboxypyranocyanidin. Ceposide A, ceposide B and ceposide C. Spiraeoside (4′ -O-glucoside of quercetin). Onionin A1 , onionin A2 , onionin A3 , onionin B1 and B2 . Onionin A1 (3,4-dimethyl-5-(1E-propenyl)tetrahydrothiophen-2-sulfoxide-S-oxide). Cyanidin 3-glucoside (Cy 3-Glc), 3-malonylglucoside (Cy3-MaGlc), cyanidin 3-laminaribioside (Cy 3-Lam) and 3-malonyllaminaribioside (Cy 3-MaLam). Bioactivity References Anti-ADP-aggregation activity in human blood platelets. Inhibition of human platelet aggregation. Cytotoxic activity against murine melanoma B16 and sarcoma XC. [148–151] Increase in the height of mouse small intestine. [152] Anti-inflammatory and immunomodulatory effect. Induction of quinone reductase. Antifungal activity. Radical scavenging, anti-inflammatory, inhibition of the expression of B-cell lymphoma 2. Suppression of tumor progression in mouse ovarian cancer (Onionin A1 ). Suppression of tumor-cell proliferation through the inhibition of polarization of M2 activated macrophages. [153–161] Molecules 2022, 27, 4475 15 of 48 Table 10. Cont. Plant Species Plant Part A. sativum. A. sativum L. var. voghiera. A. sativum L. Root, protobulb, leaf sheath and blade, bulbs, tuber A. schoenoprasum Whole plant, pale-purple flowers A. minutiflorum Regel Bulbs A. neapolitanum Extracts Country Isolated Compounds Bioactivity References Italy Nerolidol, α-pinene, terpinolene. Voghieroside A1/A2, voghieroside B1/B2, voghieroside C1/C2, voghieroside D1/D2 and voghieroside E1/E2. Adenosine and guanosine. Antifungal activity against Sclerotium cepivorum. Antimicrobial activity. Strong inhibitory effect on human platelet aggregation generated by 2 µM ADP in both primary and secondary waves (adenosine). [162–164] Cytotoxicity against HCT 116 and HT-29 human colon cancer lines. [165,166] Antifungal activity. [167] Antiplatelet aggregation activity. [168] (20S, 25S)-spirost-5-en-3β, 12β,21-triol 3-O-α-Lrhamnopyranosyl-(1→2)-β-D-glucopyranoside, (20S, 25S)-spirost-5-en-3β, 11α,21-triol 3-O-α-Lrhamnopyranosyl-(1→2)-β-D-glucopyranoside, laxogenin 3-O-α-L-rhamnopyranosyl–(1→2)-[β-Dglucopyranosyl-(1→4)]-[β-D-glucopyranoside, (25R)-5α-spirostan-3β, 11α-diol 3-O-β-Dglucopyranosyl-(1→4)]-β-D-galactopyranoside. (cyanidin 3-O-β-glucosideAII) (kaempferol 3-O-(2-O-βglucosylFIII-β-glucosideFII)-7-O-β-glucosiduronic acid FIV) malonate AIII (AII-6→AIII-1, FIV-2→AIII-3), 1, (cyanidin 3-O-(3-O-acetyl-β-glucosideAII) (kaempferol 3-O-(2-O-β-glucosylFIII-β-glucosideFII)7-O-β-glucosiduronic acid FIV) malonate AIII (AII-6→AIII-1, FIV-2→AIII-3), 2, and 7-O-(methyl-O-β-glucosiduronateFIV). Minutoside A, minutoside B, Minutoside C, alliogenin, neoagigenin 3-O-{[2-O-α-1-rhamnopyrnosyl-4-O-β-Dglucopyranosyl]-β-D-glucopyranoside}, isorhamnetin; 3-O-{[2-O-α-1-rhamnopyrnosyl-6-O-β-Dglucopyranosyl]-β-D-glucopyranoside}, isorhamnetin; 3-O-{[2-O-α-1-rhamnopyranosyl-4-O-β-Dglucopyranosyl]-β-D-glucopyranoside}-7-O-β-Dglucopyranoside and isorhamnetin; 3-O-{[2-O-α-1-rhamnopyranosyl-6-O-β-Dgentiobiosyl]-β-D-glucopyranoside}. Molecules 2022, 27, 4475 16 of 48 Table 10. Cont. Plant Species Plant Part A. tripedale Bulbs, leaves A. porrum L. Bulbs A. chinense. A. chinense G. Don Bulbs Country Iran Isolated Compounds 6,7-dimethoxy-N-trans-caffeoyltyramine; N-trans-feruloyltyramine. (+)-S-(1-butenyl)-L-cysteine sulfoxide (homoisoalliin), S-(1-butenyl)-L-cysteine (desoxyhomoisoalliin). Kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-β-Dgalactopyranosyl]-(1→4)-O-β-D-glucopyranoside; Kaempferol 3-O-[2-O-(trans-3-methoxy-4-hydroxycinnamoyl)-β-Dglucopyranosyl]-(1→6)-O-β-D-glucopyranoside. (25R)-5 α-spirostan-3 β, 6 β-diol 3-O-[O-β-D-glucopyranosyl(1→2)-O-[β-D-xylopyranosyl-(1→3)]-O-β-Dglucopyranosyl-(1→4)-β-D-galactopyranoside}; (25R)-5 α-spirostan-3 β, 6 β-diol 3-O-{O-β-D-glucopyranosyl-(1→3)-O-β-D-glucopyranosyl(1→2)-O-[β-D-xylopyranosyl-(1→3)]-O-β-Dgalactopyranosyl-(1→4)-β-D-galactopyranoside} Chinenoside II and chinenoside III. (25 R,S)-5 α-Spirostan-3β-ol tetrasaccharide, (25R)-3 β-hydroxy-5 α-spirostan-6-one di- and tri-saccharides. Xiebai-saponin I (laxogenin 3-O-β-xylopyranosyl (1→4)-[α-arabinopyranosyl (1→6)-β-glucopyranoside), laxogenin 3-O-α-arabinopyranosyl (1→6)-β-glucopyranoside, laxogenin, isoliquiritigenin, isoliquiritigenin-4-O-glucoside, and β-sitosterol glucoside. Bioactivity References NR. [167,168] Antiplatelet aggregation activity. Antifungal activity. [169–171] Inhibition of cAMP phosphodiesterase. Antitumor-promoting activity (laxogenin). [172–175] Molecules 2022, 27, 4475 17 of 48 Table 10. Cont. Plant Species A. macrostemon. A. macrostemon Bunge Plant Part Bulbs, leaves Country Isolated Compounds Bioactivity References Japan Macrostemonoside G (26-O-β-D-glucopyranosyl-22-hydroxy5-β-furost-25(27)-ene-3 β,12 β,26 triol 3-O-β-D-glucopyranosyl(1–>2)-β-D-galactopyranoside) and I (26-O-β-D-glucopyranosyl-22-hydroxy-5 β-furost-25(27)-ene-12-one-3 β,26-diol 3-O-β-D-glucopyranosyl(1→2)-β-D-galactopyranoside). tigogenin-3-O-β-D-glucopyranosyl(1–>2) [β-D-glucopyranosyl(1→3)1]-β-D-glucopyranosyl(1→4)-βD -galactopyranoside (1) and tigogenin-3-O-β-D-glucopyranosyl(1→2)[β-Dglucopyranosyl (1→3)(6-O-acetyl-β-D-glucopyranosyl)] (1→4)-β-D-galactopyranoside (2). Macrostemonoside E-(25R)-26-O-β-D-glucopyranosyl-5 α-furost-20(22)-ene-3 β,26-diol-3-O-β-D-glucopyranosyl (1→2) [β-D-glucopyranosyl (1→3)]-β-D-glucopyranosyl (1→4)-β-D-galactopyranoside; Macrostemonoside F(II)-(25R)-26-O-β-D-glucopyranosyl-5 β-furost-20(22)-ene-3 β,26-diol-3-O-β-D-glucopyranosyl (1→2)-β-D-galactoside. Allimacronoid A (1-O-(E)-feruloyl-β-D-glucopyranosyl (1-2)-[β-D-glucopyranosyl (1-6)]-β-D-glucopyranose), Allimacronoid B (1-O-(E)-feruloyl-{β-D-glucopyranosyl (1-4)-[β-D-glucopyranosyl (1-2)]}-[β-D-glucopyranosyl (1-6)]-β-D-glucopyranose) and Allimacronoid Cn1-O-(E)-feruloyl-{β-D-glucopyranosyl (1-6)-[β-D-glucopyranosyl (1-2)]}-[β-D-glucopyranosyl (1-6)]-β-D-glucopyranose. In vitro inhibition of ADP-induced human platelet aggregation (macrostemonoside G). Inhibitory activity against rabbit platelet aggregation induced by ADP (1). [176–179] Molecules 2022, 27, 4475 18 of 48 Table 10. Cont. Plant Species Plant Part A. schubertii Bulbs A. tuberosum Seeds Country Shanghai Isolated Compounds (25R and S)-5 α-spirostan-2 α,3 β,6 β-triol 3-O-β-D-glucopyranosyl-(1→2)-O-[4-O-benzoyl-β-Dxylopyranosyl-(1→3)]-O-β-D-glucopyranosyl-(1→4)-β-Dgalactopyranoside, (25R and S)-5 α-spirostan-2α,3β,6 β-triol 3-O-β-D-glucopyranosyl-(1→2)-O-[3-O-benzoyl-β-Dxylopyranosyl-(1→3)]-O-β-D-glucopyranosyl-(1→4)-β-Dgalactopyranoside, (25R and S)-5 α-spirostan-2α,3β,6 β-triol 3-O-β-D-glucopyranosyl-(1→2)-O-[4-O-(3S)-3-hydroxy-3methylglutaroyl-β-D-xylopyranosyl-(1→3)]-O-β-Dglucopyranosyl-(1→4)-β-D-galactopyranoside and 26-O-β-D-glucopyranosyl-(25R and S)-5 α-furostan-2α,3β,6β,22 zeta,26-pentol 3-O-β-Dglucopyranosyl-(1→2)-O-[β-D-xylopyranosyl-(1→3)]-O-βD -glucopyranosyl-(1→4)-β- D -galactopyranoside. (2α, 3β, 5α, 25S)-2,3,27-trihydroxyspirostane 3-O-α-L-rhamnopyranoyl-(1→2)-O-[α-L-rhamnopyranosyl(1→4)]-β-D-glucopyranoside. Tuberoside J-(25R)-5 α-spirostan-2α,3 β,27-triol 3-O-α-L-rhamnopyranosyl-(1–>2)-β-D-glucopyranoside; Tuberoside K-(25R)-5α-spirostan-2α,3β 27-triol 3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl(1→4)]-β-D-glucopyranoside; and Tuberoside L-27-O-β-D-glucopyranosyl-(25R)-5α-spirostan-2α,3 β,27-triol 3-O-α-D-rhamnopyranosyl-(1–>2)-[α-Lrhamnopyranosyl-(1→4)]-β-D-glucopyranoside. Tuberoside M-(25S)-5β-spirostane-β,3 β-diol 3-O-α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside. Tuber-ceramide (N-(2′ ,3′ -dihydroxy-tetracosenoyl)-2-amino-1,3,4-trihydroxy octadecane), and Cerebroside (N-(2′ ,3′ -dihydrox-tetra-cosenoyl)-2-amino-1,3,4-trihydroxy octadecane). Bioactivity References NR. [180] Tuberoside M inhibits the proliferation of the human promyelocytic leukemia cell line (HL-60) [181–183] Molecules 2022, 27, 4475 19 of 48 Table 10. Cont. Plant Species A. albopilosum and A. ostrowskianum Plant Part Country Bulbs A. fistulosum. A. fistulosum L. Whole plant, leaves, seeds Iran A. carolinianum DC Bulb Mongolia Isolated Compounds (25 R and S)-5 α-spirostane-2α, 3 β,6 β-triol 3-O-(O-β-D-glucopyranosyl-(1→2)-O-[3-O-acetyl-β-Dxylopyranosyl-(1→3)]-O-β-D-glucopyranosyl-(1→4)-β-Dgalactopyranoside), (25R)-2-O-[(S)-3-hydroxy-3-methylglutaroyl]-5 α-spirostane-2α, 3β, 6β-triol 3-O-(O-β-D-glucopyranosyl(1→2)-O-[β-D-xylopyranosyl-(1— >3)]-O-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside), (22S)-cholest-5-ene-1β, β,16 β,22-tetraol 1-O-α-L-rhamnopyranoside 16-O-(O-α-L-rhamnopyranosyl(1→3)-β-D-glucopyranoside), 1β, 3β, 16β-trihydroxycholest-5-en-22-one 1-O-aα-L-rhamnopyranoside 16-O-(O-α-L-rhamnopyranosyl(1→3)-β-D-glucopyranoside), 1β,3β,16 bβ-trihydroxy-5 α-cholestan-22-one 1-O-α-L-rhamnopyranoside 16-O-(O-α-Lrhamnopyranosyl-(1→3)-β-D-glucopyranoside) and (22S)-cholest-5-ene-1β,3β, 16β,22-tetraol 16-O-(O-β-D-glucopyranosyl-(1→3)-β-D-glucopyranoside). Fistulomidate A ((1Z,2E)-Methyl3-(3,4-dimethoxyphenyl)-N(4-hydroxyphenethyl) acrilimidate) and Fistulomidate B ((1Z,2E)-Methyl3-(3,4-dihydroxyphenyl)-N-(4hydroxyphenethyl)acrilimidat). Onionin A1 , onionin A2 , and onionin A3 . Glycerol mono-(E)-8,11,12-trihydroxy-9-octadecenoate, tianshic acid, 4-(2-formyl-5-hydroxymethylpyrrol-1-yl) butyric acid, p-hydroxybenzoic acid, vanillic acid, and daucosterol. Cinnamoylphenethylamine derivative Bioactivity References NR. [184] Antibacterial and cytotoxic activity. Suppression of tumor progression in mouse ovarian cancer (onionin A1 ). Inhibition of the growth of Phytophtohora capsici on V8 media (glycerol mono-(E)-8,11,12-trihydroxy-9-octadecenoate and V). [159,185,186] Weak cytotoxic activity [187] Molecules 2022, 27, 4475 20 of 48 Table 10. Cont. Plant Species Plant Part A. ampeloprasum var. porrum (Leek) Plant parts A. ascalonicum L. Country China A.siculum Bulbs Zwanenburg, The Netherlands A.chrysanthum Barks Guangzhou, China A. L. melanocrommyum section Megaloprason. Bulbs Central Asia Isolated Compounds Bioactivity References A-β- D -glucopyranoside Anticancer activity against MCF-7 human breast cancer cell. [187] NR. [188,189] NR. [190] NR. [191] NR. [192] Ascalonicoside C-(25R)-26-O-β-D-glucopyranosyl-22hydroxy-5α-furost-2-one-3β,5,6β, 26-tetraol-3-O-α-L-rhamnopyranosyl-(1→2)-β-Dglucopyranoside. Ascalonicoside D -(25R)-26-O-β- D -glucopyranosyl-22-methoxy-5α-furost-2one-3β,5,6β, 26-tetraol-3-O-α-L-rhamnopyranosyl-(1→2)-β-Dglucopyranoside. (25R)-26-O-β-D-glucopyranosyl-22-hydroxy-5-ene-furostan3β,26-diol-3-O-α-L-rhamnopyranosyl-(1→4)-α-Lrhamnopyranosyl-(1→4)-[ α-L-rhamnopyranosyl-(1→2)]-β-D-glucopyranoside. 25R)26-O-β-D-glucopyranosyl-22-hydroxy-5-ene-furostan-3β, 26-diol-3-O-α-L-rhamnopyranosyl-(1→2)-[α-Larabinofuranosyl-(1→4)]-β-D-glucopyranoside. (Z)-Butanethial S-oxide, (R(S),R(C),E)-S-(1-butenyl)cysteine S-oxide (homoisoalliin). Chrysanthumones A (6′′ ,6′′ -dimethyl-4′′ ,5′′ -dihydropyrano [2′′ ,3′′ : 8,7]-6”′ ,6′′′ -dimethyl-prenyl-4′′′ ,5′′′ -dihydropyrano [2′′′ ,3′′′ :2′ ,3′ ]apigenin) and B ((E)-5,7-dihydroxy-2-(4-hydroxyphenyl)-8-(3-methylbut-1enyl)-4H-chromen-4-one). L-(+)-S-(2-pyridyl)-cysteine sulfoxide. Molecules 2022, 27, 4475 21 of 48 Table 10. Cont. Plant Species Plant Part Country Isolated Compounds Bioactivity References United States of America Ampeloside Bs1 (apigenin 3-O-β-glucopyranosyl (1 → 3)-β-glucopyranosyl (1 → 4)-β-galactopyranoside), ampelosides Bf1 ((25R)-26-O-β-glucopyranosyl-22-hydroxy5α-furostane-2α,3β,6β,26-tetraol-3-O-β-glucopyranosyl(1 → 3)-β-glucopyranosyl-(1 → 4)-β-galactopyranoside) and Bf2 ((25R)-26-O-β-glucopyranosyl-22-hydroxy-5α-furostane2α,3β,6β,26-tetraol-3-O-β-glucopyranosyl(1 → 4)-β-galactopyranoside). Weak antifungal activity by ampeloside Bs1 . [193] Adenosine, guanosine, and tryptophan, β-sitosterol β-D-glucoside. Strong inhibitory effect on human platelet aggregation generated by 2 µM ADP in both primary and secondary waves (adenosine). [162] Cytotoxic activity. [194] NR. [195] A. ampeloprasum L. Bulbs A. bakeri Reg. Tuber A.victorialis var. platyphyllum Aerial parts, bulbs A. nutans L. Underground plant parts A.giganteum Bulbs Japan A. hookeri Thwaites Rhizomes China NR: not reported. Korea Gitogenin 3-O-lycotetroside, astragalin and kaempferol 3, 4′ -di-O-β-D-glucoside. Deltoside, nolinofuroside D, 25R ∆(5)-spirostan 3β-ol-3-O-α-L-rhamnopyranosyl(1–>2)-[β-Dglucopyranosyl(1→4)]-O-β-D-galactopyranoside and 25R ∆(5)-spirostan 1 β, 3β-diol 1-O-β-D-galactopyranoside. 3-O-acetyl-(24S,25S)-5α-spirostane-2α,3β,5α,6β,24-pentol 2-O-β-D-glucopyranoside. Di-2-propenyl trisulfide, diallyl disulfide, and dipropyl trisulfide. Inhibition of cAMP phosphodiesterase activity. Antimicrobial activity against Aspergillus fumigatus and C. albicans. [196] [197] α α β α β Molecules 2022, 27, 4475 β 22 of 48 The chemical structures of compounds from the genus Allium are shown in Figure 4. Figure 4. Chemical structures of compounds isolated from the genus Allium. Quercetin (13), vanillic acid (14) and adenosine (15). 3.4. Pharmacological Effects of Allium There are several species within Allium whose biological activities have been well established [198]. This section focuses on the pharmacological activities associated with these species. 3.4.1. Antimicrobial Activities Garlic has shown antimicrobial effects against Gram-positive, Gram-negative and acid fast stain organisms [199–201]. Allicin from garlic showed effectiveness toward methicillinresistant S. aureus (MRSA) [200]. Extracts from garlic also showed broad-spectrum fungicidal effect against several fungi including Candida, Trichophyton, Cryptococcus, Aspergillus, Trichosporon and Rhodotorula species. Garlic extract was recently found to inhibit Meyerozyma guilliermondii and Rhodotorula mucilaginosa germination and growth [202]. A study by Fufa reported the antifungal activity of various A. sativum extracts, namely aqueous, ethanol, methanol, and petroleum ether against human pathogenic fungi such are Trichophyton verrucosum, T. mentagrophytes, T. rubrum, Botrytis cinereal (B. cinerea), Candida species, Epidermophyton floccosum, A. niger, A. flavus, Rhizopus stolonifera, Microsporum gypseum, M. audouinii, Alternaria alternate, Neofabraea alba, and Penicillium expansum [203]. Essential oil from garlic showed antifungal activity against a number of fungi such as (C. albicans, C. tropicalis and Blastoschizomyces capitatus). Saponins extracted from A. sativum had antifungal activity against B. cinerea and Trichoderma harzianum [204]. Allium species from Ghana were reported by Danquah et al. to possess anti-infective and resistance modulatory effects on selected microbial strains [205]. Allium hirtifolium was found to exhibit antimicrobial activities against E. faecalis [206]. Previous studies have shown that garlic extract inhibit the growth of Blastocystis species in vivo and this effect was attributed to the several phytochemicals contained in garlic extracts. Examples of these phytochemicals are thiosulfinates and allicin which have been investigated to possess antibacterial and antiprotozoal effects [204,207]. Garlic extracts have been evaluated for antiviral effects against influenza B, human rhinovirus type 2, human cytomegalovirus (HCMV), parainfluenza virus type 3, Herpes simplex type 1 and -2, vaccinia virus, and vesicular stomatitis virus [208]. Danquah et al. again reported the antitubercular effects of analogues of disulfides from A. stipitatum as well as their antibiofilm and anti-efflux effects [209]. 3.4.2. Antioxidant Properties It has been reported that frequent garlic intake promotes internal antioxidant activities and reduces oxidative adverse effects either by increasing the endogenous antioxidant synthesis or reducing the production of oxidizing agents such as oxygen-free radical species (ORS) [210]. It has also been demonstrated that garlic possesses protective properties against gentamycin as well as acetaminophen-induced hepatotoxicity by improving antioxidant status, and regulating oxidative stress [200]. Garlic extract was found to elevate the activities of selected antioxidant enzymes (e.g., superoxide dismutase (SOD)) and decrease Molecules 2022, 27, 4475 23 of 48 glutathione peroxidase (GSH-Px) in rats’ hepatic tissues [13,118,211]. Saponins extracted from garlic were reported to scavenge intracellular ROS and protect mouse-derived C2 C12 myoblasts towards growth inhibition and H2 O2 -induced DNA damage [13,212]. A. ursinum aqueous extract also demonstrated antioxidant effect which lasted approximately 16 h [213]. A. hirtifolium was reported to possess antioxidant capacity by neutralizing the free radical species in a system [214]. 3.4.3. Anti-Inflammatory Properties It has been reported widely that garlic extracts and its related phytochemicals possess anti-inflammatory activity. A study by Ahmad et al. revealed that garlic extracts significantly impaired liver inflammation and damage caused by Eimeria papillata infections [215]. The mechanism underlying the anti-inflammatory effects of garlic was attributed to the inhibition of emigration of neutrophilic granulocytes into epithelia as described by Hobauer et al. [216] and Gu et al. [217]. The chloroform extract of aged black garlic acts by reducing NF-κB activation in human umbilical vein endothelial cells caused by tumor necrosis factor-α (TNF-α) and the methanolic extract also reported to prevent the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2 ) production by NF-κB inactivation [218]. A report by Jin et al. confirmed that thiacremonone (a sulfur compound isolated from garlic) prevents neuroinflammation and amyloidogenesis by blocking the NF-κB activity, and therefore makes it an ideal remedy to manage neurodegenerative disorders (e.g., Alzheimer’s disease) related to inflammation [219]. Krejčová et al. reported that pyrithione and related sulfur-containing pyridine Noxides from Persian shallot possessed anti-inflammatory and neurological activity [220]. The extracts of A. stipitatum were reported to exhibit antibacterial effect in vivo against methicillin-resistant S. aureus [221]. Anti-inflammatory effect of A. hookeri on carrageenaninduced air pouch mouse model was also established by Kim et al. [222]. 3.4.4. Anticancer Activity Comparison of the anticancer effect of raw garlic extracts against other extracts from different plants found garlic to be the most effective and highly specific anticancer agent [223]. The anticancer mechanisms of garlic extracts were reported to be mediated via inhibition of cell growth and proliferation, regulation of carcinogen metabolism, stimulation of apoptosis, prevention of angiogenesis, invasion, and migration; and thus affording the anticancer agent with minimal negative effects [13]. Chabria et al. reported that allicin isolated from garlic suppresses colorectal cancer metastasis through enhancing immune function and preventing the formation of tumor vessels as well as surviving gene expression to enhance the cancer cell’s apoptosis [224]. Fleischauer and Arab [225] reported that continuous garlic intake could decrease different kinds of cancer propagation such as cancer of the lung, colon, stomach, breast, and prostate. Piscitelli et al. reported that garlic reduced the plasma concentrations of saquinavir by approximately 50% in healthy participants after a 3-week garlic supplement intake. In addition to this, many researchers evaluated the antitumor and cytotoxic actions of garlic and its related constituents in vitro and in vivo [226]. 3.4.5. Other Pharmacological Effects of Allium Species Investigations on extracts of A. sativum (garlic) revealed anticholinesterase effects, which could be further developed and utilized in the management of Alzheimer’s disease [227–229]. Garlic is known to possess hypolipidemic effects by reducing the total glycosaminoglycans concentration in heart and aorta [230]. Garlic is also known to reduce the level of cholesterol either by acid stimulation and excretion of neutral steroids or by reducing the cholesterogenic and lipogenic effects of fatty acid synthase, 3-hydroxy-3methyl-glutaryl-CoA reductase, malic acid, and glucose-6 phosphate dehydrogenase in hepatocytes [231]. Garlic tablets formulated by Ashraf et al. and administered at a dose of Molecules 2022, 27, 4475 24 of 48 600 mg/day for 12 weeks in diabetic patients with dyslipidemia resulted in high HDL, low LDL and TC levels [232]. Allicin, a constituent in garlic, was found to reduce diabetes mellitus in rats, which was similar to that demonstrated by glibenclamide and insulin [233]. Garlic extracts reduce body weight, adipose tissue mass and improved plasma lipid profiles in mice with high-fat diet-induced obesity [234]. The mechanism of these activities is downregulation of multiple gene expression such as adipogenesis along with upregulation of the mitochondrial inner membrane proteins expression [234]. Garlic extract is widely known to significantly control blood pressure by reducing both systolic and diastolic pressures [235]. Moreover, several reports have confirmed the antihypertensive effects of garlic [236]. Extracts of A. stipitatum were also assessed and established to possess significant wound healing properties [237]. 4. The Genus Crinum 4.1. Geographical Distribution of Crinum Crinum, which also belongs to the Amaryllidaceae family, comprises approximately 160 beautiful lilies that grow naturally in coastal areas of the tropics and subtropics. They are widely distributed in Africa, Asia, Australia and America [238–241] 4.2. Traditional Uses of Crinum Plants of the genus Crinum have been used to treat various diseases across the world [242]. In China and Vietnam, Crinum plants in traditional medicine are believed to possess antiviral and immune-stimulatory properties. A hot aqueous extract of Crinum latifolium (C. latifolium) is used as an antitumor agent. Crinum asiaticum (C. asiaticum) is used in Malaysia to treat rheumatism and to relieve local pain [239]. Crinum amabile Donn. (C. amabile) is used in Vietnam to induce emesis, as well as for rheumatism and earache [241]. The bulbs of C. asiaticum L. are used as a tonic, laxative and expectorant in Indian traditional medicine, as well as for treating urinary tract diseases [241]. The seeds are used as purgatives, diuretics, and tonics, while the raw roots are used as an emetic. The leaves are also very useful in the management of skin problems, inflammation and cough [241]. C. latifolium L. is also used to treat rheumatism, abscesses, earaches, and as a tonic. Crinum pratense (C. pratense) and Crinum longifolium (C. longifolium) are also used as bitter tonics, laxatives and in the management of chest illnesses [243]. Crinum zeylanicum (C. zeylanicum) L. is used in Sri Lanka to treat abscesses and fevers; the bulbs are also used as rubefacient in rheumatism and against snake bites; and the juice from the leaves used to treat earaches [244]. The roots of Crinum species have been used in African traditional medicine to cure urinary infections, coughs and colds, renal and hepatic disorders, ulcers, sexually transmitted infections, and backache, as well as enhance breastfeeding in both animal and human mothers [241]. Crinum kirkii Bak. (C. kirkii), a widespread East African grassland plant, is used to heal wounds in Kenya. In Tanzania, the fruit and inner part of the bulbs are used as purgatives, and the outer scales employed as rat poison [245,246]. Extracts of Crinum delagoense (C. delagoense) Verdoorn is utilized in Zulu and Xhosa traditional medicine in South Africa to treat urinary tract infections and body oedema [247–249]. Rheumatism, aching joints, septic sores, varicose veins, and kidney and bladder infections have all been treated using the South African Crinum bulbispermum (C. bulbispermum) [250]. In Cameroon, Crinum pupurascens (C. pupurascens) Herb is used to treat sexual asthenia and spleen disorders. Crinum species (C. defixum Keraudren et Gawl., C. firmifolium Baker, C. modestum Baker) are as well used in Madagascar to treat abscesses, anthrax, and otitis. It is also employed as an emetic, diaphoretic, and emollient. Externally, Crinum firmifolium (C. firmifolium) is used to treat a variety of parasite skin afflictions [40,243]. Molecules 2022, 27, 4475 25 of 48 4.3. Phytochemistry of Crinum Several phytochemical and pharmacological studies have been conducted on the genus Crinum. The compounds isolated from various species of Crinum as well as their biological activities have been outlined in Table 11. Molecules 2022, 27, 4475 26 of 48 Table 11. Bioactive compounds isolated from Crinum species. Plant Species Plant Part Country C. x amabile C. x amabile Donn ex Ker Gawl Bulbs Stems, roots Ecuador Brazil Thailand C. defixum Ker-Gawl Bulbs India C. moorei Bulblets C. biflorum Bulbs C. asiaticum C. asiaticum var. sinicum C. asiaticum L. C. asiaticum var. japonicum. C. asiaticum L. var. sinicum. Seeds, rhizome, fruits Bulbs, stems, leaves Senegal Beijing, China, Hainan Province, Japan, Island of Jeju in Korea Isolated Compounds Haemanthamine/crimine-type alkaloid. Lycorine-type alkaloid Galanthamine-type alkaloid. Augustine N-oxide, buphanisine N-oxide. Amabiloid A. Hydrazide derivative. (E)-N-[(E)-2-butenoyl]-2-butenoylhydrazide. Cherylline, crinamidine, crinine, epibuphanisine, lycorine, powelline, undulatine, 1-epideacetylbowdensine, 3-O-acetylhamayne. 3-[4′ -(8′ -aminoethyl) phenoxy] bulbispermine, mooreine. 5,6,7-trimethoxy-3-(4 hydroxybenzyl) chroman-4-one, 3-hydroxy-5,6,7-trimethoxy-3-(4-hydroxybenzyl) chroman-4-one, 3-hydroxy-5,6,7-trimethoxy-3-(4-methoxybenzyl) chroman-4-one, 5,6,7-trimethoxy-3-(4-methoxybenzyl) chroman-4-one, (E)-N-(4-hydroxyphenethyl)-3-(4-hydroxyphenyl) acrylamide. Flavonoids Isopowellaminone. (2R,3S)-7-methoxyflavan-3-ol (1:), (2R,3S)-7-hydroxy-flavan-3-ol (2:), (2R,3S)-2 ′ -hydroxy-7-methoxy-flavan-3-ol (3:). Norgalanthamine. Crinamine CAL-n. Crijaponine A, crijaponine B, ungeremine, lycorine, 2-O-acetyllycorine, 1,2-O-diacetyllycorine, (-)-crinine, 11-hydroxyvittatine, hamayne,(+)-epibuphanisine, crinamine, yemenine A, epinorgalanthamine. Criasiaticidine A, pratorimine, Lycorine, 4′ -hyd’oxy-7-methoxyflavan. Crinamine, lycorine, norgalanthamine, epinorgalanthamine. Asiaticumines A, asiaticumines B. Bioactivity References Anticholinesterase (anti-AChE) and antibutyrylcholinesterase (anti-BuChE) activity. [249–251] Anti-genotoxic activity. [252] NR. [253] Anticancer, anti-AChE, anti-glucosidase activity. [254,255] Inhibitory activity against LPS-induced nitric oxide production. Anticancer activity (against cervical cancer SiHa cells). Inhibition of platelet aggregation. Promotion of hair growth through dermal papilla proliferation. Inhibition of the growth of HepG2 tumor cells. Anti-AChE activity, cytotoxic activity. Cytotoxic against Meth-A (mouse sarcoma) and Lewis lung carcinoma (mouse lung carcinoma). Inhibition of the activity of hypoxia inducible factor-1 (crinamine). Cytotoxicity. [256–266] Molecules 2022, 27, 4475 27 of 48 Table 11. Cont. Plant Species Plant Part Country C. kirkii Baker Bulbs C. macowanii Bulbs C. firmifolium Leaves Madagascar C. latifolium Bulbs Leaves China. Hanoi, Vietnam C. scillifolium Bulbs C. zeylanicum (L) Bulbs, leaves, flowers, fruits Cuba Sri Lanka C. jagus (J. Thomps) Dandy Bulbs, leaves Senegal Ghana C. abyscinicum Hochst. ExA. Rich Bulbs Ethiopia C. erubescens Above ground plant parts C. yemense Bulbs Puntarenas, Costa Rica Yemen Isolated Compounds Bioactivity References Noraugustamine, 4aN-dedihydronoraugustamine, 3-O-acetylsanguinine, 1,2-diacetyllycorine. Antiparasitic activity against Trypanosoma brucei (T. brucei) rhodesiense, Trypanosoma cruzi (T. cruzi). [267,268] NR. [249] Antiplasmodial activity. [269] Cytotoxic against tumor cell lines, antimicrobial activity, antioxidant activity. Inhibitory activity against human umbilical venous endothelial cells. [270–272] Mild antiplasmodial activity [273] Antiproliferative effect. [246,274] Anti-AChE activity, inhibitors of TcAchE, hAChE and hBChE [275,276] 6-hydroxycrinamine, lycorine. Antiproliferative activity against A2780 epithelial ovarian cancer and MV4-11 acute myeloid leukemia cell lines. [277] Cripowellin A, cripowellin B, cripowellin C, cripowellin D, hippadine. Antiplasmodial activity. [278] 6-hydroxy-2H-pyran-3-carbaldehyde. Yemenines A, B and C, 1, (+)-bulbispermine, (+)-crinamine, (+)-6-hydroxycrinamine, (-)-lycorine. Tyrosinase inhibitor. Inhibit nitric oxide production, induce nitric oxide synthase. [277–280] Macowine, lycorine, cherylline, crinine, krepowine, powelline, buphanidrine, crinamidine, undulatine, 1-epideacetylbowdensine, 4a-dehydroxycrinamabine. 2-alkylquinolin-4(1H), 2-alkylquinolin-4(1H). 4,8-dimethoxy-cripowellin C. 4,8-dimethoxy-cripowellin D, 9-methoxy-cripowellin B, 4-methoxy-8-hydroxy-cripowellin B, cripowellin C. C. latines A, C. latines B and C. latines C. 4-senecioyloxymethyl-3,4-dimethoxycoumarin, 5,6,3 ′ -trihydroxy-7,8,4 ′ -trimethoxyflavone. 4-methyloxysenecioyl-6,7-dimethoxycoumarin, 5,6,3′ -trihydroxy-7,8,4′ trimethoxyflavone. Scillitazettine, scilli-N-desmethylpretazettine. Crinine, Lycorine, 11-O-acetoxyambelline, ambelline, 6-hydroxybuphanidrine, 6-ethoxybuphanidrine, 3-acetylhamayne, 6-hydroxycrinamine, hamayne, 6-methoxycrinamine. Gigantelline, gigantellinine, gigancrinine, sanguinine, cherylline, lycorine, crinine, flexinine, hippadine. Galanthamine, galanthamine N-oxide, powelline. Molecules 2022, 27, 4475 28 of 48 Table 11. Cont. Plant Species Plant Part Country C. bulbispermum C. bulbispermum III Bulbs Egypt C. powellii Bulbs Switzerland Colombia C. glaucum Bulbs Nigeria C. purpurascens Leaves Cameroon NR: not reported. Isolated Compounds 8-hydroxylycorin-7-one, 2-deoxylycorine, vittatine, 11-hydroxyvittatine, hippamine. 4-hydroxy-2′ ,4′ -dimethoxydihydrochalcone, 4,5-methylenedioxy-4′ -hydroxy-2-aldehyde [1,1′ -biphenyl], hippacine, 4′ -hydroxy-7-methoxyflavan-3-ol, ′ ′ 2(S),3 ,4 -dihydroxy-7-methoxy flavan, isolarrien, isoliquiritigenin, liquiritigenin. Bulbispermine. Linoleic acid ethyl ester, alkaloid hippadine, calleryanin, 4′ -hydroxy-7-methoxyflavan. Lycorine, 1-O-acetyllycorine, ismine. Hamayne, lycorine, haemanthamane, crinamine. 4,5-ethano-9,10-methlenedioxy-7-phenanthridone, 4,5-ethano-9-hydroxy-10-methoxy-7-phenanthridone, α-D-glucopyranoside. Bioactivity References NR. [281–283] AChE inhibitor (linoleic acid ethyl ester). Inhibition of topoisomerase 1 activity. [284,285] Choline esterase inhibitory activity. [286] Antibacterial activity [287] α Molecules 2022, 27, 4475 29 of 48 Chemical structures of common compounds from Crinum are shown in Figure 5. Figure 5. Chemical structures of compounds isolated from the genus Crinum. Lycorine (16), crinamine (17), galantamine (18) and crinine (19). 4.4. Pharmacological Activities of Crinum 4.4.1. Anti-Inflammatory and Analgesic Effects The anti-inflammatory and the analgesic properties of various Crinum species have been investigated by several authors. The anti-inflammatory effect of C. asiaticum as well as its effect on bradykinin-induced contractions on isolated uterus has been reported [288–291]. The ethanolic extract of C. asiaticum demonstrated significant analgesic effect in an aceticacid-induced writhing test [292]. Antipyretic and anti-inflammatory properties of C. jagus were recently reported by Minkah and Danquah [291]. Leaf extract of C. bulbispermum has also been established to possess antinociceptive effects [293,294]. 4.4.2. Anticancer and Cytotoxicity Effects The cytotoxic effects of C. asiaticum extract was investigated and was shown to exert toxic effect on brine shrimps and murine P388 D1 cells [294–298]. Yui et al. demonstrated that hot water extracts of C. asiaticum exhibited potent inhibition of calprotectin-induced cytotoxicity in MM46 mouse mammary carcinoma cells. This activity whi1ch was later attributed to lycorine, an active compound in C. asiaticum [297]. Some alkaloids isolated from the bulbs of C. asiaticum have been reported to show remarkable inhibition against tumor cell lines A549, LOVO, HL-60, and 6T-CEM [261]. The extract of C. asiaticum exhibited antiproliferative and chemosensitizing effects against multi-drug-resistant cancer cells [298,299]. The antiangiogenic activity of the methanolic leaf extract of C. asiaticum was evaluated and established by Yusoff [300]. The cytotoxic effect of the essential oil extracted from C. asiaticum was as well established in MCF-7 cells [301]. A recent work done by Yu et al. reported the inhibition of the growth of HepG 2 cells in a dose-dependent manner by polysaccharide CAL-n, an isolate from C. asiaticum [262]. Also, the neuroprotection and anti-neuroinflammatory effects in Neuronal Cell Lines were reported by Lim et al. [279,302]. Alkaloids from C. bulbispermum have also been reported to possess cytotoxic activities [284]. Evaluation of the cytoprotective potential of C. bulbispermum, after induction of toxicity using rotenone, in SH-SY5Y neuroblastoma cells proved that, the plant has such effect as reported [303]. Aboul-Ela et al. [279] tested the cytotoxic effect of C. bulbispermum bulbs using the brine shrimp bioassay. 4.4.3. Antimicrobial Properties The in vitro antitubercular effects of C. asiaticum on Mycobacterium tuberculosis (M. tuberculosis) surrogate, Mycobacterium smegmatis (M. smegmatis), were reported [291,304]. C. asiaticum was shown to possess a broad-spectrum antimicrobial activity against Grampositive, Gram-negative bacteria and fungal pathogens [291,299]. Antifungal activities of the essential oil and extracts of C. asiaticum against pathogenic fungi have also been established [305,306]. It is reported that the methanolic root extract of C. asiaticum exerts significant anti-HIV-1 activity [307]. The ethanolic extract of C. asiaticum significantly inhibited Molecules 2022, 27, 4475 30 of 48 selected bacteria as evaluated by Naira et al. [308]. Dichloromethane extract of C. asiaticum was found to be the most effective against selected oral and vaginal Candida species [309]. Minkah and Danquah again demonstrated the antimicrobial activity of extracts of C. jagus against clinically significant microorganisms in the High-throughput spot culture growth inhibition (HT-SPOTi) assay [291]. Water/Ethanol extract of C. jagus was observed to be active on Shigella flexneri-induced diarrhea in rats [310]. The antimicrobial and antioxidant properties of C. jagus make it suitable as a wound healing agent [311]. The crude methanolic extract of C. jagus was investigated to have effect on Mycobacterium tuberculosis [312,313]. The crude alkaloid of C. jagus inhibited Dengue virus infection [314]. C. macowanii has also been shown to possess biological effects such as antifungal, antiviral and antiplasmodial activities [315]. 4.4.4. Antioxidant Properties There antioxidant effects of C. asiaticum have been studied extensively. The ethanolic extract exhibited protective effects on human erythrocyte [316]. C. asiaticum bulbs also exerted remarkable free radical scavenging ability [317]. The antioxidant activity of the ethanolic extract of C. asiaticum leaves in alloxan-induced diabetic rats was well demonstrated [318]. More recent work on the methanolic extract of C. asiaticum showed antioxidant effects [319]. Potent DPPH radical scavenging activity was also observed for the aqueous C. asiaticum leaf extract [304]. Both the leaves and bulbs of C. jagus are important sources of antioxidant compounds [320]. A methanolic bulb extract of C. bulbispermum showed mild radical scavenging activity [321]. The leaf extracts of C. bulbispermum also showed modest antioxidant activity in a thiobarbituric acid reactive substances assay [297]. 4.4.5. Other Pharmacological Properties Kumar reported the wound healing activities of the ethanolic C. asiaticum extract. The extract was found to possess pro-healing effects when topically applied on animal models by influencing various stages of healing process [322]. C asiaticum extract and norgalanthamine potentially influenced hair growth via inhibition of 5α-reductase activity and TGF-β1-induced canonical pathway [39,314]. There is a report on the inhibitory effects of three C. asiaticum genotypes against key enzymes implicated in the pathogenesis of Alzheimer’s disease and diabetes [319]. The anti-obesity effect of the C. asiaticum extract on a high-fat diet-induced obesity in monogenic mice has been reported [323,324]. An active fraction of C. jagus was shown to possess anticonvulsant activities in experimental rats [325]. Ethyl acetate and methanol extracts of C. bulbispermum have also been shown to exhibit acetylcholinesterase inhibitory properties [321]. The alkaloid galanthamine isolated from C. bulbispermum and other genera of Amaryllidaceae, has been approved for the treatment of Alzheimer’s disease [326]. Cognitive enhancing effect of a hydroethanolic extract of C. macowanii against memory impairment induced by aluminum chloride in balb/c mice has as well been reported [327]. 5. The Genus Cyrtanthus 5.1. Botanical Description Another large genus of the family Amaryllidaceae is Cyrtanthus. Cyrtanthus is derived from a Greek word for curved flower [6]. Species of this genus have numerous, black, winged seeds and give off a strong onion smell [6]. They possess a rhizome or bulb, flowers and a loculicidal capsule fruit [6]. They have leaves that are linear to lorate [6]. Flowers are funnel shaped with their stamens fixed in the corolla tube [6]. Species that belong to this genus include Cyrtanthus elatus (C. elatus) (Jacq.) Traub, Cyrtanthus obliquus (C. obliquus) (L.f.) Aiton, and Cyrtanthus mackenii (C. mackenii) Hook [44]. Molecules 2022, 27, 4475 31 of 48 5.2. Geographical Distribution Cyrtanthus is diverse and is a large sub-Saharan Africa genus consisting of approximately 55 species found mostly in South Africa. Cyrtanthus extends from the summer-dry southwest to the summer rainfall northeast [328]. The genus displays diverse floral morphology. The three major lineages show varying biogeographic affinities. Clade A comprises taxa located in Southern African Grassland Biome with a few outliers in the Savanna Biome to the east and north, the Indian Ocean Coastal Belt Biome to the extreme east and the Fynbos Biome to the south [328]. Hence, it falls in the Afrotemperate Phytogeographical Region [329] that encompasses Afromontane phytochorion in the north and the Cape Floristic Region in the south [328]. Most existing species in the Afrotemperate lineage (Cyrtanthus attenuatus (C. attenuatus), Cyrtanthus macowanii (C. macowanii), Cyrtanthus epiphyticus (C. epiphyticus), C. mackenii subsp. cooperi, Cyrtanthus huttonii (C. huttonii), Cyrtanthus macmasteri (C. macmasteri), Cyrtanthus suaveolens (C. suaveolens), Cyrtanthus stenanthus (C. stenanthus var. stenanthus) and Cyrtanthus flanaganii (C. flanaganii) occur currently in the south-eastern African temperate grasslands. Cyrtanthus tuckii var. transvaalensis (C. tuckii) is the only species found in the grassland of the Highveld in the northern parts of South Africa. Few species are found outside this grassland area and includes Cyrtanthus angustifolius (C. angustifolius), Cyrtanthus fergusoniae (C. fergusoniae) and Cyrtanthus aureolinus (C. aureolinus) in the Cape Region together with C. mackenii subsp. Mackenii and Cyrtanthus brachyscyphus (C. brachyscyphus) that occupies drainage lines on the subtropical Indian Ocean Coastal Belt [330]. Southern Africa is the area where Cyrtanthus breviflorus (C. breviflorus) is found extending northwards in a series of disjunct populations along mountain corridors to East Africa and Angola. Clade B is limited to the Fynbos and Succulent Karoo Biomes which constitute the Greater Cape Region, referred to hereafter as ‘the Cape’ [331]. Cyrtanthus labiatus (C. labiatus) and Cyrtanthus montanus (C. montanus) from the Baviaansklo of Mountains and Eastern Cape are found at the interface of the Fynbos and Albany Thicket Biomes. The Richtersveld species, Cyrtanthus herrei (C. herrei) is found in the semi-arid Succulent Karoo [328]. Most species found in ‘the Cape’ lineage are located on the summer-dry, southeast coast forelands with half the number in the Fynbos of the nonseasonal rainfall Eastern Cape. Cyrtanthus carneus (C. carneus, C. elatus, Cyrtanthus guthrieae (C. guthrieae, C. labiatus, Cyrtanthus leptosiphon (C. leptosiphon), Cyrtanthus leucanthus (C. leucanthus, Cyrtanthus montanus (C. montanus), and Cyrtanthus odorus (C. odorus) are found in specific vegetation types and soils. Only two species of this taxon, namely Cyrtanthus collinus (C. collinus) and Cyrtanthus ventricosus (C. ventricosus) are well known, inhabiting the same soils and aspect in habitats on the continuous Cape Fold mountain ranges [328]. Cyrtanthus collinus is found on the coastal and inland mountains of the southern Cape and C. ventricosus extends from the Cape Peninsula into the Eastern Cape [328]. Most species of Clade C are found in the eastern lowlands and midlands of southern Africa, where they are concentrated in the subtropical biomes, Albany Thicket and Savanna [330,332]. This lineage constitutes Cyrtanthus flammosus (C. flammosus) and Cyrtanthus spiralis (C. spiralis), which are narrowly widespread to the Albany Thicket Biome. Confined to the Savanna Biome are Cyrtanthus eucallus (C. eucallus) and Cyrtanthus galpinii (C. galpinii) in the Lowveld. Other species span the Albany Thicket and Savanna Biomes: the Eastern Cape Cyrtanthus helictus (C. helictus) and, extending northwards from the Albany region through South Africa, Zimbabwe, western Mozambique and East Africa into Sudan, is Cyrtanthus sanguineus (C. sanguineus) [328]. Cyrtanthus obliquus, adapted to nutrient-poor soils, occupies rocky habitats in east–west tending valleys. A summary of their geographic distribution is presented in Table 12. Molecules 2022, 27, 4475 32 of 48 Table 12. Geographical distribution of the Genus Cyrtanthus. Lineage Location Clade A Southern Africa Grassland Southeastern African temperate grasslands Grassland of the Highveld in the northern parts Subtropical Indian Ocean Coastal Belt East Africa and Angola Clade B Baviaanskloof Mountains and Eastern Cape (Fynbos and Albany Thicket Biomes) Semi-arid Succulent Karoo Greater Cape Region (“the Cape”) Coastal and inland mountains of the southern Cape Cape Peninsula into the Eastern Cape Clade C Albany Thicket Biome Savanna Biome Northwards from the Albany region through South Africa, Zimbabwe, Western Mozambique and East Africa into Sudan Albany Thicket and Savanna Biomes Extends beyond the Savanna Biome into the Sub-Escarpment and Highveld grasslands Fynbos Biome Southern parts of the Nama Karoo Species C. attenuatus, C. macowanii, C. epiphyticus, C. mackenii subsp. cooperi, C. huttonii, C. macmasteri, C. suaveolens, C. stenanthus var. stenanthus, C. flanaganii C. tuckii var. transvaalensis C. angustifolius, C. fergusoniae C. aureolinus, C. mackenii subsp. Mackenii, C. brachyscyphus C. breviflorus C. labiatus, C. montanus C. herrei C. carneus, C. elatus, C. guthrieae, C. labiatus, C. leptosiphon, C. leucanthus, C. montanus, C. odorus C. collinus C. ventricosus C. flammosus, C. spiralis C. eucallus, C. galpinii C. sanguineus C. helictus C. contractus C. wellandii C. smithiae References [328] [328] [328] 5.3. Traditional Uses Cyrtanthus obliquus, locally known as umathunga in South Africa, is used traditionally in the management of chronic coughs, headaches and scrofula [43,44]. C. obliquus root infusions are also employed in the management of stomach aches [333] while the crushed roots have been reported to find use in the management of leprosy [334]. Cyrtanthus species are also employed in the management of ailments associated with pregnancy, as well as cystitis, age-related dementia and leprosy [43,44]. Bulbs of C. contractus extracted in May and September is widely used locally in the management of mental illness, infections, inflammation, and cancer [335]. Infusions from species such as C. breviflorus, C. contractus, C. mackenii, C. sanguineus, C. stenanthus and C. tuckii are used by the Zulu in South Africa as protective sprinkling charms against storms and evil spirits [336]. Extracts of C. breviflorus Harv. are used as an anti-emetic agent and in the management of worm infestations such as tapeworm and roundworm. Extracts of C. elatus also finds use in the management of cough, headache and in labour induction [337]. 5.4. Phytochemistry of Cyrtanthus Species of Cyrtanthus have been identified as reservoirs for a host of chemical compounds. In a study performed by Mahlangeni et al., four homoisoflavanones, namely 5,7dihydroxy-6-methoxy-3-(4′ -methoxybenzyl)chroman-4-one, 5,7-dihydroxy-6-methoxy-3(4′ hydroxybenzyl)chroman-4-one and two 5,7-dihydroxy-6-methoxy-3-(4′ -methoxybenzylidene)chroman-4-one, 5,7-dihydroxy-3-(4′ hydroxybenzylidene)-chroman-4-one were isolated from the hexane, methanol and dichloromethane extracts of Cyrtanthus obliquus [338]. The bulbs of C. obliquus extracted with ethanol also revealed the presence of novel alkaloid obliquine, as well as 1α-hydroxygalanthamine, 3-epimacronine, narcissidine, tazettine and trisphaeridine [339]. The presence of lycorine, tazettine and 11-hydroxyvittatine in dried bulb ethanol extract of Cyrtanthus mackenii (Hook f.) has been demonstrated by Masi et al. [340]. Fresh bulb methanol extracts of C. contractus also contains a phenanthridone alkaloid called narciclasine [335]. Furthermore, two crinine alkaloids; haemanthamine and haemanthidine Molecules 2022, 27, 4475 33 of 48 have been isolated from fresh bulb ethanol extracts of C. elatus. Further studies on the alcoholic extracts of the fresh bulbs also yielded the alkaloids zephyranthine, galanthamine and 1,2-O-diacetylzephyranthine [43,44]. Tazettine, maritidine, O-methylmaritidine, and papyramine are all phytochemicals that have been identified in fresh bulb methanol extracts of C. falcatus [337]. Chemical structure of compounds isolated from Cyrtanthus have been shown in Figure 6. Figure 6. Chemical structures of selected compounds from Crytanthus. Zephyranthine (20), 1,2-O-diacetylzephyranthine (21), haemanthamine (22), haemanthadine (23), galanthamine (18), ꞌ ꞌ ′ 5,7-dihydroxy-6-methoxy-3-(4′ -methoxybenzyl)chroman-4-one (24), ꞌ 5,7-dihydroxy-6-methoxy-3-(4 methoxybenzylidene)chroman-4-one (25), 5,7-dihydroxy-6-methoxy-3-(4′ hydroxybenzyl)chromanꞌ ′ 4-one (26), 5,7-dihydroxy-3-(4 hydroxybenzylidene)-chroman-4-one (27) and naciprimine (28). 5.5. Pharmacological Activities 5.5.1. Antioxidant Activity ′ 5,7-dihydroxy-6-methoxy-3-(4′ -methoxybenzyl)chroman-4-one and 5,7-dihydroxy-6′ methoxy-3-(4′ -hydroxybenzyl)chroman-4-one isolated from the fresh bulbs of C. obliquus have been shown to possess significant antioxidant activity with an IC50 of 371.54 and 288.40 µg/mL, respectively [338]. 5.5.2. Anti-Inflammatory Activity The methanol extract of the bulbs of C. contractus has been investigated and shown to possess significant anti-inflammatory activity. The extract exhibited dose-dependent inhibition of E-selectin, a proinflammatory agent, when tested on endothelial cells. Further studies of the methanol extract on human umbilical vein endothelial cells revealed a concentration-dependent reduction in THP-1 adhesion via blockade of the expression of endothelial adhesion molecule ICAM-1. Narciclasine was identified as the main antiinflammatory compound in the methanol extract of the bulbs of C. contractus [335]. The dichloromethane (DCM) extracts of C. falcatus (roots) and C. mackenii (leaves) were shown to interfere with the activity of cyclooxygenase 2 (COX-2) by at least 90%. DCM extract of C. suaveolens also blocked prostaglandin synthesis via antagonizing COX-2 activity by 81.6 %. Moderate inhibition (approximately 70%) of COX-2 activity was also observed with the methanol extracts of the roots and leaves of C. falcatus [341,342]. Selective inhibition of COX-2 by these extracts makes them suitable candidates for development for clinical use. 5.5.3. Inhibition of Acetylcholinesterase The phenanthridone alkaloid nacriprimine, isolated from the ethanolic bulb extract of C. contractus has been shown to possess mild acetylcholinesterase inhibition property with Molecules 2022, 27, 4475 34 of 48 an IC50 of 78.9 µg/mL compared to the 40-fold more potent standard galanthamine with an IC50 of 1.9 µg/mL [11]. 5.5.4. Antimicrobial Activity Cyrtanthus species and their isolated compounds have demonstrated noteworthy antimicrobial activity against a panel of microorganisms. C. suaveolens bulbs/roots and leaves isolated with DCM demonstrated broad-spectrum antimicrobial activity against B. subtilis, E. coli, K. pneumoniae, M. luteus and S. aureus with zones of inhibition ranging between 0.13–0.91 mm. DCM extracts of C. falcatus also inhibited the growth of B. subtilis S. aureus and E. coli. C. mackenii bulb/root extracts also inhibited the growth M. luteus and S. aureus [337]. Haemanthamine and haemanthidine isolated from the bulbs of C. elatus have been investigated for their activity against parasitic protozoans [43]. Haemanthamine showed activity against trophozoite stage of Entamoeba histolytica (E. histolytica) HK9 with an IC50 of 0.75 µg/mL and mild activity against Plasmodium falciparum (P. falciparum) NF54 with an IC50 of 0.67 µg/mL. The activity against E. histolytica was compared to ornidazole with an IC50 0.28 µg/mL whiles the activity against P. falciparum was compared to chloroquine with an IC50 of 0.004 µg/mL and artemisinin with an IC50 of 0.002 µg/mL [43]. Haemanthidine also showed weak activity against P. falciparum, T. brucei rhodesiense STIB 900, and T. cruzi Tulahuen C4 with an IC50 of 0.70, 1.1 and 1.38 µg/mL, respectively. Melarsoprol with an IC50 of 0.002 µg/mL and benznidazole with an IC50 of 0.56 µg/mL were used as standards for Trypanosoma brucei rhodesiense STIB 900, and Trypanosoma cruzi Tulahuen C4, respectively [43]. 5.5.5. Cytotoxic Activity Haemanthamine isolated from C. elatus was shown to possess cytotoxic activity which was mediated via the apoptotic pathway as depicted in rat hepatoma cell (5123tc). The ED50 was determined at 15 µM and this result was of particular interest due to its selectivity; haemanthamine demonstrated insignificant activity in normal human embryo kidney (293t) cells [337]. Alkaloids isolated from C. obliquus tested for cytotoxic activity against Chinese Hamster ovarian and human hepatoma (hepG2) cells showed no cytotoxic activity up to a concentration of 100 µg/mL [339]. Tazettine isolated from C. falcatus and other members of Amaryllidaceae has been reported to possess cytotoxic activity on colon cell line murine alveolar non-tumoral fibroblast [343,344]. Papyramine, also extracted from C. falcatus showed cytotoxic activity against murine alveolar non-tumoral fibroblast and human lymphoid neoplasm as well [343,344]. 5.5.6. Miscellaneous Pharmacological Activities Roots of C. falcatus and C. surveolens extracted with DCM exhibited mutagenicity in Salmonella strain TA98 which was higher than that observed in the leaves of these plants. Mutagenicity was, however, not observed in the methanol extracts of these plants [337]. The mutagenicity of C. suaveolens has been attributed to the compound captan isolated from the bulbs/roots using DCM [344]. A summary of the traditional uses, phytochemicals and pharmacological activities of Cyrtanthus species have been highlighted in Table 13. Molecules 2022, 27, 4475 35 of 48 Table 13. A summary of the traditional uses, phytochemicals and pharmacological activities of Cyrtanthus species. Plant Species C. obliquus Traditional Uses Compounds Pharmacological Activities References Chronic cough, headache and scrofula 5,7-dihydroxy-6-methoxy-3-(4′ methoxybenzyl)chroman-4-one, 5,7-dihydroxy-6-methoxy-3-(4′ hydroxybenzyl)chroman-4-one Antioxidant activity [338] [337] C. contractus Mental illness, protective charm against evil spirits NarciclasineNarciprimine Anti-inflammatory activity (via inhibition of E-selectin, blockade of the expression of endothelial adhesion molecule ICAM-1)Acetylcholinesterase inhibitor C. breviflorus Emesis, worm infestations, protective charm against evil spirits haemanthamine, lycorine, crinamine hydrochloride and tazettine Antihelminthic [337,342] C. elatus Cough, headache, labor induction Antiprotozoan activity, selective cytotoxic activity [43,44,337] C. falcatus Not known to be used by the traditional South African people C. suaveolens No traditional use has been reported Haemanthamine, zephyranthine, galanthamine and 1,2-O-diacetylzephyranthine Papyramine, epipapyramine, maritidine, O-methylmaritidine and tazettine Captan Antibacterial activity against B. subtilis S. aureus and E. coli, mutagenicity, cytotoxic activity Mutagenicity, anti-inflammatory activity via inhibition of COX-2, fungicide [342–344] [342,344] 6. Conclusions The discovery of new drugs in response to the growing burden of infectious and non-communicable diseases is of utmost necessity in this era. The genera Tulbaghia, Allium, Crinum, and Cyrtanthus of the Amaryllidaceae family have been well presented and shown to be a source of promising medicinal compounds with varying biological properties. Further research is therefore necessary to propel these compounds through clinical trials for possible usage in therapeutics. Although natural products have been attributed with high safety profiles, the presence of mutagenic compounds in crude extracts of these plants underscores the importance of pharmacological studies prior to their use in traditional medicine. These findings are relevant in light of augmenting the lean pipeline of drug discovery. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules27144475/s1, Table S1: Compounds from Tulbaghia. Reference [345] is cited in the Supplementary Materials. Author Contributions: Conceptualization and study design, C.A.D. and P.A.B.M.; literature search and review, C.A.D., P.A.B.M., T.A.A., P.M., M.O., P.D., S.R., I.O.D.J., K.B.A., S.O.S., I.N.N., V.J.M., S.B. and S.G.; writing—original draft preparation, C.A.D., P.A.B.M., T.A.A., P.M., M.O., P.D., S.R., I.O.D.J., K.B.A., S.O.S., I.N.N., V.J.M., S.B. and S.G.; writing—review and editing, C.A.D., P.A.B.M., P.M., I.O.D.J., V.J.M., S.B. and S.G.; formatting and design—P.A.B.M. and P.M.; project administration, C.A.D. and P.A.B.M.; supervision, C.A.D. All authors have read and agreed to the published version of the manuscript. Funding: The authors received no specific grant from the government, private or non-profit organizations. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. Molecules 2022, 27, 4475 36 of 48 Abbreviations MIC, minimum inhibitory concentration; MBC, minimum bactericidal concentration; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide; MoA, mode of action; ROS, reactive oxygen species; TEAC, Trolox equivalent antioxidant capacity; FRAP, ferricreducing antioxidant power; DPPH, 2,2-diphenyl-1-picryl-hydrazyl-hydrate; AAPH, 2,2′ azobis-2-amidinopropane dihydrochloride; TG, triglyceride; TC, total cholesterol; VLDL, very low-density lipoprotein; HDL, high-density lipoprotein; BP, blood pressure; AVD, atherothrombotic vascular disease; DCM, dichloromethane. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Barile, E.; Capasso, R.; Izzo, A.A.; Lanzotti, V.; Sajjadi, S.E.; Zolfaghari, B. Structure-activity relationships for saponins from Allium hirtifolium and Allium elburzense and their antispasmodic activity. Planta Med. 2005, 71, 1010–1018. [CrossRef] [PubMed] Chase, M.W.; Reveal, J.L.; Fay, M.F. A subfamilial classification for the expanded asparagalean families Amaryllidaceae, Asparagaceae and Xanthorrhoeaceae. Bot. J. Linn. Soc. 2009, 161, 132–136. [CrossRef] Takos, A.M.; Rook, F. Towards a Molecular Understanding of the Biosynthesis of Amaryllidaceae Alkaloids in Support of Their Expanding Medical Use. Int. J. Mol. Sci. 2013, 14, 11713–11741. [CrossRef] [PubMed] Vosa, C.G.; Siebert, S.J.; Van Wyk, A.E.B. Micromorphology and cytology of Prototulbaghia siebertii, with notes on its taxonomic significance. Upsp. Inst. Repos. 2011, 41, 311–314. Elgorashi, E.E.; van Staden, J. Bioactivity and Bioactive Compounds of African Amaryllidaceae; ACS Publications: Washington, DC, USA, 2009; ISBN 1947-5918. Fenwick, G.R.; Hanley, A.B.; Whitaker, J.R. The genus allium—Part 1. Crit. Rev. Food Sci. Nutr. 1985, 22, 199–271. [CrossRef] Fenwick, G.R.; Hanley, A.B. The genus allium—Part 2. Crit. Rev. Food Sci. Nutr. 1985, 22, 273–377. [CrossRef] Aremu, A.O.; Van Staden, J. The genus Tulbaghia (Alliaceae)—A review of its ethnobotany, pharmacology, phytochemistry and conservation needs. J. Ethnopharmacol. 2013, 149, 387–400. [CrossRef] Styger, G.; Aboyade, O.M.; Gibson, D.; Hughes, G. Tulbaghia—A Southern African Phytomedicine. J. Altern. Complement. Med. 2016, 22, 255–261. [CrossRef] Jagtap, U.B.; Lekhak, M.M.; Fulzele, D.P.; Yadav, S.R.; Bapat, V.A. Analysis of selected Crinum species for galanthamine alkaloid: An anti-Alzheimer drug. Curr. Sci. 2014, 107, 2008–2010. Nair, J.J.; Aremu, A.O.; Van Staden, J. Isolation of narciprimine from Cyrtanthus contractus (Amaryllidaceae) and evaluation of its acetylcholinesterase inhibitory activity. J. Ethnopharmacol. 2011, 137, 1102–1106. [CrossRef] Torras-Claveria, L.; Berkov, S.; Codina, C.; Viladomat, F.; Bastida, J. Daffodils as potential crops of galanthamine. Assessment of more than 100 ornamental varieties for their alkaloid content and acetylcholinesterase inhibitory activity. Ind. Crops Prod. 2013, 43, 237–244. [CrossRef] Shang, A.; Cao, S.-Y.; Xu, X.-Y.; Gan, R.-Y.; Tang, G.-Y.; Corke, H.; Mavumengwana, V.; Li, H.-B. Bioactive Compounds and Biological Functions of Garlic (Allium sativum L.). Foods 2019, 8, 246. [CrossRef] [PubMed] Sharma, D.; Rani, R.; Chaturvedi, M.; Rohilla, P.; Yadav, J.P. In silico and in vitro approach of Allium cepa and isolated quercetin against MDR bacterial strains and Mycobacterium smegmatis. S. Afr. J. Bot. 2019, 124, 29–35. [CrossRef] Stoica, F.; Aprodu, I.; Enachi, E.; Stănciuc, N.; Condurache, N.N.; Dut, ă, D.E.; Bahrim, G.E.; Râpeanu, G. Bioactive’s Characterization, Biological Activities, and In Silico Studies of Red Onion (Allium cepa L.) Skin Extracts. Plants 2021, 10, 2330. [CrossRef] [PubMed] Albishi, T.; John, J.A.; Al-Khalifa, A.S.; Shahidi, F. Antioxidant, anti-inflammatory and DNA scission inhibitory activities of phenolic compounds in selected onion and potato varieties. J. Funct. Foods 2013, 5, 930–939. [CrossRef] Benmalek, Y.; Yahia, O.A.; Belkebir, A.; Fardeau, M.-L. Anti-microbial and anti-oxidant activities of Illicium verum, Crataegus oxyacantha ssp monogyna and Allium cepa red and white varieties. Bioengeineered 2013, 4, 244–248. [CrossRef] [PubMed] Elberry, A.A.; Mufti, S.; Al-Maghrabi, J.; Abdel Sattar, E.; Ghareib, S.A.; Mosli, H.A.; Gabr, S.A. Immunomodulatory effect of red onion (Allium cepa Linn) scale extract on experimentally induced atypical prostatic hyperplasia in Wistar rats. Mediat. Inflamm. 2014, 2014, 640746. [CrossRef] Lanzotti, V. The analysis of onion and garlic. J. Chromatogr. 2006, 1112, 3–22. [CrossRef] Rouf, R.; Uddin, S.J.; Sarker, D.K.; Islam, M.T.; Ali, E.S.; Shilpi, J.A.; Nahar, L.; Tiralongo, E.; Sarker, S.D. Antiviral potential of garlic (Allium sativum) and its organosulfur compounds: A systematic update of pre-clinical and clinical data. Trends Food Sci. Technol. 2020, 104, 219–234. [CrossRef] Harazem, R.; El Rahman, S.A.; El-Kenawy, A. Evaluation of Antiviral Activity of Allium cepa and Allium sativum Extracts Against Newcastle Disease Virus. Alex. J. Vet. Sci. 2019, 61, 108–118. [CrossRef] Elmi, T.; Hajialiani, F.; Asadi, M.R.; Sadeghi, S.; Namazi, M.J.; Tabatabaie, F.; Zamani, Z. Antimalarial effects of the hydroalcoholic extract of Allium paradoxum in vitro and in vivo. J. Parasit. Dis. 2021, 45, 1055–1064. [CrossRef] Molecules 2022, 27, 4475 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 37 of 48 Ruslan, M.S.; Baba, M.S. In vivo antimalarial assessment and toxicity evaluation of garlic (Allium sativum) in plasmodium berghei NK65-induced mice. Malays. Appl. Biol. 2018, 47, 17–24. Syaban, M.F.R.; Rachman, H.A.; Arrahman, A.D.; Hudayana, N.; Khamid, J.P.; Pratama, F.A. Allium sativum as antimalaria agent via falciapin protease-2 inhibitor mechanism: Molecular docking perspective. Clin. Res. J. Intern. Med. 2021, 2, 130–135. [CrossRef] Upadhyay, R.K. Nutritional and therapeutic potential of Allium vegetables. J. Nutr. Ther. 2017, 6, 18–37. [CrossRef] Thomson, M.; Ali, M. Garlic [Allium sativum]: A review of its potential use as an anti-cancer agent. Curr. Cancer Drug Targets 2003, 3, 67–81. [CrossRef] [PubMed] Corea, G.; Fattorusso, E.; Lanzotti, V.; Capasso, R.; Izzo, A.A. Antispasmodic saponins from bulbs of red onion, Allium cepa L. var. Tropea. J. Agric. Food Chem. 2005, 53, 935–940. [CrossRef] Galmarini, C.R.; Goldman, I.L.; Havey, M.J. Genomics Genetic analyses of correlated solids, flavor, and health-enhancing traits in onion (Allium cepa L.). Mol. Genet. Genom. 2001, 265, 543–551. [CrossRef] Takahashi, M.; Shibamoto, T. Chemical compositions and antioxidant/anti-inflammatory activities of steam distillate from freeze-dried onion (Allium cepa L.) sprout. J. Agric. Food Chem. 2008, 56, 10462–10467. [CrossRef] Nishimura, H.; Wijaya, C.H.; Mizutani, J. Volatile flavor components and antithrombotic agents: Vinyldithiins from Allium victorialis L. J. Agric. Food Chem. 1988, 36, 563–566. [CrossRef] Brace, L.D. Cardiovascular benefits of garlic (Allium sativum L.). J. Cardiovasc. Nurs. 2002, 16, 33–49. [CrossRef] Ali, M.; Thomson, M.; Afzal, M. Garlic and onions: Their effect on eicosanoid metabolism and its clinical relevance. Prostaglandins Leukot. Essent. Fat. Acids 2000, 62, 55–73. [CrossRef] [PubMed] Sabiu, S.; Madende, M.; Ajao, A.A.; Aladodo, R.A.; Nurain, I.O.; Ahmad, J.B. The Genus Allium (Amaryllidaceae: Alloideae): Features, Phytoconstituents, and Mechanisms of Antidiabetic Potential of Allium cepa and Allium sativum, 2nd ed.; Elsevier Inc.: Amsterdam, The Netherlands, 2019; ISBN 9780128138229. Muñoz-Torrero López-Ibarra, D. Recent Advances in Pharmaceutical Sciences I; Transworld Research Network: Trivandrum, India, 2011; ISBN 8178955288. Akash, M.S.H.; Rehman, K.; Chen, S. Spice plant Allium cepa: Dietary supplement for treatment of type 2 diabetes mellitus. Nutrition 2014, 30, 1128–1137. [CrossRef] [PubMed] Corzo-Martínez, M.; Corzo, N.; Villamiel, M. Biological properties of onions and garlic. Trends Food Sci. Technol. 2007, 18, 609–625. [CrossRef] Kumar, K.P.S.; Debjit, B.; Pankaj, T. Allium cepa: A traditional medicinal herb and its health benefits. J. Chem. Pharm. Res. 2010, 2, 283–291. Shri, R.; Bora, K.S. Neuroprotective effect of methanolic extracts of Allium cepa on ischemia and reperfusion-induced cerebral injury. Fitoterapia 2008, 79, 86–96. [CrossRef] Kongkwamcharoen, C.; Itharat, A.; Pipatrattanaseree, W.; Ooraikul, B. Effects of Various Preextraction Treatments of Crinum asiaticum Leaf on Its Anti-Inflammatory Activity and Chemical Properties. Evid. Based. Complement. Alternat. Med. 2021, 2021, 8850744. [CrossRef] [PubMed] Fennell, C.W.; Van Staden, J. Crinum species in traditional and modern medicine. J. Ethnopharmacol. 2001, 78, 15–26. [CrossRef] Maroyi, A. Ethnobotanical, phytochemical and pharmacological properties of Crinum bulbispermum (Burm f) Milne-Redh and Schweick (Amaryllidaceae). Trop. J. Pharm. Res. 2016, 15, 2497–2506. [CrossRef] Takaidza, S.; Pillay, M.; Mtunzi, F.M. Biological activities of species in the genus Tulbaghia: A review. Afr. J. Biotechnol. 2015, 14, 3037–3043. Herrera, M.R.; Machocho, A.K.; Nair, J.J.; Campbell, W.E.; Brun, R.; Viladomat, F.; Codina, C.; Bastida, J. Alkaloids from Cyrtanthus elatus. Fitoterapia 2001, 72, 444–448. [CrossRef] Nair, J.J.; van Staden, J. Chemical and biological studies of the South African Amaryllidaceae genera Crinum, Ammocharis, Amaryllis, Cyrtanthus and Brunsvigia. S. Afr. J. Bot. 2021, 142, 467–476. [CrossRef] Heinrich, M.; Teoh, H.L. Galanthamine from snowdrop—the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J. Ethnopharmacol. 2004, 92, 147–162. [CrossRef] [PubMed] Nair, J.J.; van Staden, J. Pharmacological and toxicological insights to the South African Amaryllidaceae. Food Chem. Toxicol. 2013, 62, 262–275. [CrossRef] [PubMed] Govaerts, R. World Checklist of Selected Plant Species. Facilitated by the Royal Botanic Gardens, Kew. 2015. Available online: https://wcsp.science.kew.org/about.do (accessed on 25 March 2022). Kubec, R.; Velíšek, J.; Musah, R.A. The amino acid precursors and odor formation in society garlic (Tulbaghia violacea Harv.). Phytochemistry 2002, 60, 21–25. [CrossRef] Dillon, H.; Nelson, E.C. Tulbaghia leucantha: Alliaceae. Kew Mag. 1991, 8, 12–15. [CrossRef] Makunga, N.P. Medicinal Plants of South Africa; Briza Publications: Pretoria, South Africa, 2010; Volume 105. Van Wyk, B.E. The potential of South African plants in the development of new food and beverage products. S. Afr. J. Bot. 2011, 77, 857–868. [CrossRef] Raji, I.A.; Obikeze, K.; Mugabo, P.E. Potential beneficial effects of tulbaghia violacea william henry harvey (Alliaceae) on cardiovascular system—A Review. Trop. J. Pharm. Res. 2015, 14, 1111–1117. [CrossRef] Pooley, E. A Field Guide to the Wild Flowers of KwaZulu-Natal and the Eastern Region. Natal Flora Publ. Trust. Pg 2005, 93, 630. Molecules 2022, 27, 4475 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 38 of 48 Sander, T.; Freyss, J.; Von Korff, M.; Rufener, C. DataWarrior: An open-source program for chemistry aware data visualization and analysis. J. Chem. Inf. Model. 2015, 55, 460–473. [CrossRef] Pino, J.A.; Quijano-Celís, C.E.; Fuentes, V. Volatile compounds of tulbaghia violacea harv. J. Essent. Oil-Bear. Plants 2008, 11, 203–207. [CrossRef] Ranglová, K.; Krejčová, P.; Kubec, R. The effect of storage and processing on antimicrobial activity of Tulbaghia violacea. S. Afr. J. Bot. 2015, 97, 159–164. [CrossRef] Smith, S.; Stansbie, J. Flora of Tropical East Africa. Crown Agents for Oversea Governments and Administration; CRC Press: Boca Raton, FL, USA, 2003; p. 230. Takaidza, S.; Mtunzi, F.; Pillay, M. Analysis of the phytochemical contents and antioxidant activities of crude extracts from Tulbaghia species. J. Tradit. Chin. Med. 2018, 38, 272–279. [CrossRef] Staffa, P.; Nyangiwe, N.; Msalya, G.; Nagagi, Y.P.; Nchu, F. The effect of Beauveria bassiana inoculation on plant growth, volatile constituents, and tick (Rhipicephalus appendiculatus) repellency of acetone extracts of Tulbaghia violacea. Vet. World 2020, 13, 1159–1166. [CrossRef] [PubMed] Devi, K.P.; Malar, D.S.; Nabavi, S.F.; Sureda, A.; Xiao, J.; Nabavi, S.M.; Daglia, M. Kaempferol and inflammation: From chemistry to medicine. Pharmacol. Res. 2015, 99, 1–10. [CrossRef] [PubMed] Teffo, L.S.; Aderogba, M.A.; Eloff, J.N. Antibacterial and antioxidant activities of four kaempferol methyl ethers isolated from Dodonaea viscosa Jacq. var. angustifolia leaf extracts. S. Afr. J. Bot. 2010, 76, 25–29. [CrossRef] Yang, C.; Yang, W.; He, Z.; Guo, J.; Yang, X.; Wang, R.; Li, H. Kaempferol Alleviates Oxidative Stress and Apoptosis Through Mitochondria-dependent Pathway During Lung Ischemia-Reperfusion Injury. Front. Pharmacol. 2021, 12, 11. [CrossRef] Murray, C.J. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet 2022, 388, 629–655. [CrossRef] Anand, U.; Jacobo-Herrera, N.; Altemimi, A.; Lakhssassi, N. A comprehensive review on medicinal plants as antimicrobial therapeutics: Potential avenues of biocompatible drug discovery. Metabolites 2019, 9, 258. [CrossRef] Kokoska, L.; Kloucek, P.; Leuner, O.; Novy, P. Plant-Derived Products as Antibacterial and Antifungal Agents in Human Health Care. Curr. Med. Chem. 2018, 26, 5501–5541. [CrossRef] Salam, A.M.; Quave, C.L. Opportunities for plant natural products in infection control. Curr. Opin. Microbiol. 2018, 45, 189–194. [CrossRef] Krstin, S.; Sobeh, M.; Braun, M.S.; Wink, M. Tulbaghia violacea and Allium ursinum extracts exhibit anti-parasitic and antimicrobial activities. Molecules 2018, 23, 313. [CrossRef] [PubMed] Eid, H.H.; Metwally, G.F. Phytochemical and biological study of callus cultures of Tulbaghia violacea Harv. Cultivated in Egypt. Nat. Prod. Res. 2017, 31, 1717–1724. [CrossRef] [PubMed] Kumar, P.; Mahato, D.K.; Kamle, M.; Mohanta, T.K.; Kang, S.G. Aflatoxins: A global concern for food safety, human health and their management. Front. Microbiol. 2017, 7, 2170. [CrossRef] [PubMed] Belewa, V.; Baijnath, H.; Frost, C.; Somai, B.M. Tulbaghia violacea Harv. plant extract affects cell wall synthesis in Aspergillus flavus. J. Appl. Microbiol. 2017, 122, 921–931. [CrossRef] Somai, B.M.; Belewa, V.; Frost, C. Tulbaghia violacea (Harv) Exerts its Antifungal Activity by Reducing Ergosterol Production in Aspergillus flavus. Curr. Microbiol. 2021, 78, 2989–2997. [CrossRef] Pretorius, J.C. Extracts and Compounds from Tulbaghia Violacea and Their Use as Biological Plant Protecting Agents 2014. Google Patents US8697149B2, 15 April 2014. Ncise, W.; Daniels, C.W.; Etsassala, N.G.E.R.; Nchu, F. Interactive effects of light intensity and ph on growth parameters of a bulbous species (Tulbaghia violacea l.) in hydroponic cultivation and its antifungal activities. Med. Plants 2021, 13, 442–451. [CrossRef] Ncise, W.; Daniels, C.W.; Nchu, F. Effects of light intensities and varying watering intervals on growth, tissue nutrient content and antifungal activity of hydroponic cultivated Tulbaghia violacea L. under greenhouse conditions. Heliyon 2020, 6, 3906. [CrossRef] [PubMed] Malungane, M.M.F.; Florah, M.M. Effect of Crude Extracts of Tulbaghia violacea (Wild Garlic) on Growth of Tomato and Supression of Meloidogyne Species; University of Limpopo: Mankweng, South Africa, 2014. Kaushik, I.; Ramachandran, S.; Prasad, S.; Srivastava, S.K. Drug rechanneling: A novel paradigm for cancer treatment. In Seminars in Cancer Biology; Elsevier: Amsterdam, The Netherlands, 2021; Volume 68, pp. 279–290. Cragg, G.M.; Grothaus, P.G.; Newman, D.J. Impact of natural products on developing new anti-cancer agents. Chem. Rev. 2009, 109, 3012–3043. [CrossRef] Mthembu, N.N.; Motadi, L.R. Apoptotic potential role of Agave palmeri and Tulbaghia violacea extracts in cervical cancer cells. Mol. Biol. Rep. 2014, 41, 6143–6155. [CrossRef] Motadi, L.R.; Choene, M.S.; Mthembu, N.N. Anticancer properties of Tulbaghia violacea regulate the expression of p53-dependent mechanisms in cancer cell lines. Sci. Rep. 2020, 10, 12924. [CrossRef] Rivas-García, L.; Romero-Márquez, J.M.; Navarro-Hortal, M.D.; Esteban-Muñoz, A.; Giampieri, F.; Sumalla-Cano, S.; Battino, M.; Quiles, J.L.; Llopis, J.; Sánchez-González, C. Unravelling potential biomedical applications of the edible flower Tulbaghia violacea. Food Chem. 2022, 381, 132096. [CrossRef] Molecules 2022, 27, 4475 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 39 of 48 Bianchini, G.; Balko, J.M.; Mayer, I.A.; Sanders, M.E.; Gianni, L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol. 2016, 13, 674–690. [CrossRef] [PubMed] Dlamini, Z.; Alouna, M.; Hull, R.; Penny, C. Abstract 2843: The effects of extracts of the indigenous South African plant, Tulbaghia violacea, on triple negative breast cancer cells. In Proceedings of the NCRI Cancer Conference, London, UK, 8–12 November 2021. Deepak, K.G.K.; Vempati, R.; Nagaraju, G.P.; Dasari, V.R.; Nagini, S.; Rao, D.N.; Malla, R.R. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol. Res. 2020, 153, 104683. [CrossRef] [PubMed] Takaidza, S.; Kumar, A.M.; Ssemakalu, C.C.; Natesh, N.S.; Karanam, G.; Pillay, M. Anticancer activity of crude acetone and water extracts of Tulbaghia violacea on human oral cancer cells. Asian Pac. J. Trop. Biomed. 2018, 8, 456–462. [CrossRef] Lyantagaye, S.L. Two new pro-apoptotic glucopyranosides from Tulbaghia violacea. J. Med. Plants Res. 2013, 7, 2214–2220. [CrossRef] Lyantagaye, S. Characterization of the Biochemical Pathway of Apoptosis Induced by D-glucopyranoside Derivatives from Tulbaghia violacea. Annu. Res. Rev. Biol. 2014, 4, 962–977. [CrossRef] Lushchak, V.I. Free radicals, reactive oxygen species, oxidative stress and its classification. Chem. Biol. Interact. 2014, 224, 164–175. [CrossRef] Thorpe, G.W.; Fong, C.S.; Alic, N.; Higgins, V.J.; Dawes, I.W. Cells have distinct mechanisms to maintain protection against different reactive oxygen species: Oxidative-stress-response genes. Proc. Natl. Acad. Sci. USA 2004, 101, 6564–6569. [CrossRef] Lourenço, S.C.; Moldão-Martins, M.; Alves, V.D. Antioxidants of natural plant origins: From sources to food industry applications. Molecules 2019, 24, 4132. [CrossRef] Madike, L.N.; Pillay, M.; Popat, K.C. Antithrombogenic properties of Tulbaghia violacea–loaded polycaprolactone nanofibers. J. Bioact. Compat. Polym. 2020, 35, 102–116. [CrossRef] Arhin, I.; Depika, D.; Ajay, B.; Delon, N.; Irene, M. Biochemical, phytochemical profile and angiotensin-1 converting enzyme inhibitory activity of the hydro-methanolic extracts of Tulbaghia acutiloba harv. J. Nat. Remedies 2019, 19, 221–235. [CrossRef] Madike, L.N.; Pillay, M.; Popat, K.C. Antithrombogenic properties of: Tulbaghia violacea aqueous leaf extracts: Assessment of platelet activation and whole blood clotting kinetics. RSC Adv. 2021, 11, 30455–30464. [CrossRef] [PubMed] Glovaci, D.; Fan, W.; Wong, N.D. Epidemiology of Diabetes Mellitus and Cardiovascular Disease. Curr. Cardiol. Rep. 2019, 21, 1–8. [CrossRef] [PubMed] Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047–1053. [CrossRef] Matheus, A.S.D.M.; Tannus, L.R.M.; Cobas, R.A.; Palma, C.C.S.; Negrato, C.A.; Gomes, M.D.B. Impact of diabetes on cardiovascular disease: An update. Int. J. Hypertens. 2013, 2013, 653789. [CrossRef] [PubMed] Moodley, K.; Joseph, K.; Naidoo, Y.; Islam, S.; Mackraj, I. Antioxidant, antidiabetic and hypolipidemic effects of Tulbaghia violacea Harv. (wild garlic) rhizome methanolic extract in a diabetic rat model. BMC Complement. Altern. Med. 2015, 15, 408. [CrossRef] [PubMed] Moodley, K.; Mackraj, I. Metabolic effects of tulbaghia violacea harv. In a diabetic model. Afr. J. Tradit. Complement. Altern. Med. 2016, 13, 113–122. [CrossRef] Raji, I.; Obikeze, K.; Mugabo, P. Comparison of the acute effects of Tulbaghia violacea William Henry Harvey (Alliaceae) on blood pressure and heart rate of ageing male normotensive Wistar kyoto rats and adult male spontaneously hypertensive rats. Trop. J. Pharm. Res. 2016, 15, 2429–2434. [CrossRef] Moodley, K.; Naidoo, Y.; Mackraj, I. Effects of Tulbaghia violacea Harv. (Alliaceae) rhizome methanolic extract on kidney function and morphology in Dahl salt-sensitive rats. J. Ethnopharmacol. 2014, 155, 1194–1203. [CrossRef] Navar, L.G. The role of the kidneys in hypertension. J. Clin. Hypertens. 2005, 7, 542–549. [CrossRef] Davì, G.; Patrono, C. Platelet Activation and Atherothrombosis. N. Engl. J. Med. 2007, 357, 2482–2494. [CrossRef] [PubMed] Masoud, K.A.A.; Okobi, E.; Ekpo, G.J. Amabeoku Investigation of Some Possible Mechanisms Involved in the Anticonvulsant Activity of Tulbaghia violacea Harv. J. Pharm. Pharmacol. 2017, 5. [CrossRef] Madike, L.N.; Takaidza, S.; Ssemakalu, C.; Pillay, M. Genotoxicity of aqueous extracts of Tulbaghia violacea as determined through an Allium cepa assay. S. Afr. J. Sci. 2019, 115, 1–6. [CrossRef] Madike, L.N.; Takaidza, S.; Ssemakalu, C.C.; Pillay, M. The effect of extracts of Tulbaghia violacea on the proliferation of a murine macrophage cell line. S. Afr. J. Bot. 2020, 130, 185–197. [CrossRef] Stavělíková, H. Morphological characteristics of garlic (Allium sativum L.) genetic resources collection—Information. Hortic. Sci. 2008, 35, 130–135. [CrossRef] Wheeler, E.J.; Mashayekhi, S.; Mcneal, D.W.; Travis Columbus, J.; Chris Pires, J. Molecular systematics of Allium subgenus Amerallium (Amaryllidaceae) in North America. Am. J. Bot. 2013, 100, 701–711. [CrossRef] Fernandes, S.; Gois, A.; Mendes, F.; Perestrelo, R.; Medina, S.; Câmara, J.S. Typicality Assessment of Onions (Allium cepa) from Different Geographical Regions Based on the Volatile Signature and Chemometric Tools. Foods 2020, 9, 375. [CrossRef] Jo, J.; Purushotham, P.M.; Han, K.; Lee, H.-R.; Nah, G.; Kang, B.-C. Development of a Genetic Map for Onion (Allium cepa L.) Using Reference-Free Genotyping-by-Sequencing and SNP Assays. Front. Plant Sci. 2017, 8, 1342. [CrossRef] Najeebullah, S.; Shinwari, Z.K.; Jan, S.A.; Khan, I.; Ali, M. Ethno medicinal and phytochemical properties of genus Allium: A review of recent advances. Pak. J. Bot. 2021, 53, 135–144. [CrossRef] Lawande, K.E. Onion. In Handbook of Herbs and Spices; Elsevier: Amsterdam, The Netherlands, 2012; pp. 417–429. Molecules 2022, 27, 4475 40 of 48 111. Debin, W.; Jiande, G.; Guangshu, L. General situation of Allium crops in China. In Proceedings of the IV International Symposium on Edible Alliaceae 688, Beijing, China, 21–26 April 2004; pp. 327–332. 112. Food and Agriculture Organization of the United Nations. Available online: http://www.fao.org/faostat/en/#data (accessed on 26 March 2022). 113. Bartolucci, F.; Iocchi, M.; De Castro, O.; Conti, F. Allium ducissae (A. subgen. Polyprason, Amaryllidaceae) a New Species from the Central Apennines (Italy). Plants 2022, 11, 426. [CrossRef] 114. Friesen, N. The genus Allium L. in the flora of Mongolia. Feddes Repert. 1995, 106, 59–81. [CrossRef] 115. Sinitsyna, T.A. Genus Allium L.(Alliaceae) in Siberia. Vavilovia 2020, 2, 3–22. [CrossRef] 116. Temperate Plants Database, Ken Fern. Available online: https://temperate.theferns.info/ (accessed on 26 March 2022). 117. Kawano, S.; Nagai, Y. Life-history monographs of Japanese plants. 4: Allium victorialis L. ssp. platyphyllum (Makino) Hultén (Alliaceae) Syn. Allium victorialis L. var. platyphyllum Makino; A. latissimum Prokh. Plant Species Biol. 2005, 20, 219–225. [CrossRef] 118. Kitamura, S.; Murata, G.; Hori, M. Coloured Illustrations of Herbaceous Plants of Japan; Hoikusha Publishing Co.: Osaka, Japan, 1958. 119. Arifin, N.S.; Okudo, H. Geographical distribution of allozyme patterns in shallot (Allium cepa var. ascalonicum Backer) and wakegi onion (A. × wakegi Araki). Euphytica 1996, 91, 305–313. [CrossRef] 120. Bah, A.A.; Wang, F.; Huang, Z.; Shamsi, I.H.; Zhang, Q.; Jilani, G.; Hussain, S.; Hussain, N.; Ali, E. Biology Phyto-characteristics, Cultivation and Medicinal Prospects of Chinese Jiaotou (Allium chinense). Int. J. Agric. Biol. 2012, 14, 650–657. 121. Blattner, F.R.; Friesen, N. Relationship between Chinese Chive (Allium tuberosum) and Its Putative Progenitor A. Ramosum as Assessed by Random Amplified Polymorphic DNA (RAPD); California University Press: Los Angeles, CA, USA, 2006; pp. 134–142. 122. Pandey, A.; Pradheep, K.; Gaikwad, A.B.; Gupta, R.; Malav, P.K.; Rai, M. Systematics study on a morphotype of Allium tuberosum Rottler ex Spreng. (Alliaceae) from Ladakh, India. Indian J. Plant Genet. Resour. 2019, 32, 223–231. [CrossRef] 123. Sajad, M.A.; Khan, M.S.; Bahadur, S.; Naeem, A.; Ali, H.; Batool, F.; Shuaib, M.; Khan, M.A.S.; Batool, S. Evaluation of chromium phytoremediation potential of some plant species of Dir Lower, Khyber Pakhtunkhwa, Pakistan. Acta Ecol. Sin. 2020, 40, 158–165. [CrossRef] 124. Keusgen, M.; Fritsch, R.M.; Hisoriev, H.; Kurbonova, P.A.; Khassanov, F.O. Wild Allium species (Alliaceae) used in folk medicine of Tajikistan and Uzbekistan. J. Ethnobiol. Ethnomed. 2006, 2, 18. [CrossRef] [PubMed] 125. Ijaz, F.; Iqbal, Z.; Rahman, I.U.; Alam, J.; Khan, S.M.; Shah, G.M.; Khan, K.; Afzal, A. Investigation of traditional medicinal floral knowledge of Sarban Hills, Abbottabad, KP, Pakistan. J. Ethnopharmacol. 2016, 179, 208–233. [CrossRef] 126. Ajaib, M.; Ishtiaq, M.; Bhatti, K.H.; Hussain, I.; Maqbool, M.; Hussain, T.; Mushtaq, W.; Ghani, A.; Azeem, M.; Khan, S.M.R.; et al. Inventorization of traditional ethnobotanical uses of wild plants of Dawarian and Ratti Gali areas of District Neelum, Azad Jammu and Kashmir Pakistan. PLoS ONE 2021, 16, e0255010. [CrossRef] 127. Islam, M.; Inamullah, A.I.; Akhtar, N.; Alam, J.; Razzaq, A.; Mohammad, K.; Mahmood, T.; Khan, F.U.; Muhammad Khan, W.; Ishtiaq, A.; et al. Medicinal plants resources of Western Himalayan Palas Valley, Indus Kohistan, Pakistan: Their uses and degrees of risk of extinction. Saudi J. Biol. Sci. 2021, 28, 3076–3093. [CrossRef] [PubMed] 128. Amjad, M.S.; Qaeem, M.F.; Ahmad, I.; Khan, S.U.; Chaudhari, S.K.; Malik, N.Z.; Shaheen, H.; Khan, A.M. Descriptive study of plant resources in the context of the ethnomedicinal relevance of indigenous flora: A case study from Toli Peer National Park, Azad Jammu and Kashmir, Pakistan. PLoS ONE 2017, 12, e0171896. [CrossRef] [PubMed] 129. Tavares, L.; Santos, L.; Zapata Noreña, C.P. Bioactive compounds of garlic: A comprehensive review of encapsulation technologies, characterization of the encapsulated garlic compounds and their industrial applicability. Trends Food Sci. Technol. 2021, 114, 232–244. [CrossRef] 130. Zhao, X.X.; Lin, F.J.; Li, H.; Li, H.B.; Wu, D.T.; Geng, F.; Ma, W.; Wang, Y.; Miao, B.H.; Gan, R.Y. Recent Advances in Bioactive Compounds, Health Functions, and Safety Concerns of Onion (Allium cepa L.). Front. Nutr. 2021, 8, 463. [CrossRef] [PubMed] 131. Beretta, H.V.; Bannoud, F.; Insani, M.; Berli, F.; Hirschegger, P.; Galmarini, C.R.; Cavagnaro, P.F. Relationships Between Bioactive Compound Content and the Antiplatelet and Antioxidant Activities of Six Allium Vegetable Species. Food Technol. Biotechnol. 2017, 55, 266–275. [CrossRef] 132. Majewski , M. Allium sativum: Facts and myths regarding human health. Rocz Panstw Zakl Hig. 2014, 65, 1–8. [PubMed] 133. Marrelli, M.; Amodeo, V.; Statti, G.; Conforti, F. Biological Properties and Bioactive Components of Allium cepa L.: Focus on Potential Benefits in the Treatment of Obesity and Related Comorbidities. Molecules 2019, 24, 119. [CrossRef] 134. Teshika, J.D.; Zakariyyah, A.M.; Zaynab, T.; Zengin, G.; Rengasamy, K.R.; Pandian, S.K.; Fawzi, M.M. Traditional and modern uses of onion bulb (Allium cepa L.): A systematic review. Crit. Rev. Food Sci. Nutr. 2019, 59, S39–S70. [CrossRef] 135. Turati, F.; Pelucchi, C.; Guercio, V.; La Vecchia, C.; Galeone, C. Allium vegetable intake and gastric cancer: A case-control study and meta-analysis. Mol. Nutr. Food Res. 2015, 59, 171–179. [CrossRef] 136. Zhou, X.F.; Ding, Z.S.; Liu, N.B. Allium vegetables and risk of prostate cancer: Evidence from 132,192 subjects. Asian Pac. J. Cancer Prev. 2013, 14, 4131–4134. [CrossRef] 137. Turati, F.; Guercio, V.; Pelucchi, C.; La Vecchia, C.; Galeone, C. Colorectal cancer and adenomatous polyps in relation to allium vegetables intake: A meta-analysis of observational studies. Mol. Nutr. Food Res. 2014, 58, 1907–1914. [CrossRef] [PubMed] 138. Guercio, V.; Turati, F.; La Vecchia, C.; Galeone, C.; Tavani, A. Allium vegetables and upper aerodigestive tract cancers: A meta-analysis of observational studies. Mol. Nutr. Food Res. 2016, 60, 212–222. [CrossRef] [PubMed] 139. Kuete, V. Moringa oleifera, in Medicinal Spices and Vegetables from Africa. Med. Spices Veg. Afr. 2017, 43, 605–610. Molecules 2022, 27, 4475 41 of 48 140. Peltola, R. Allium victoralis. Available online: https://portal.mtt.fi/portal/page/portal/mtt/hankkeet/BARENTSPEC (accessed on 20 March 2022). 141. Shafakatullah, N.; Chandra, M. Isolation of lactic acid bacteria from Allium cepa var. aggregatum and study of their probiotic properties. Int. J. Pharma Sci. Res. 2015, 6, 749–752. 142. Lawless, J.W.; Latham, M.C.; Stephenson, L.S.; Kinoti, S.N.; Pertet, A.M. Iron supplementation improves appetite and growth in anemic Kenyan primary school children. J. Nutr. 1994, 124, 645–654. [CrossRef] 143. Lee, Y.M.; Lim, D.Y.; Choi, H.J.; Jung, J.I.; Chung, W.Y.; Park, J.H.Y. Induction of cell cycle arrest in prostate cancer cells by the dietary compound isoliquiritigenin. J. Med. Food 2009, 12, 8–14. [CrossRef] 144. Kaiser, P.; Youssouf, M.S.; Tasduq, S.A.; Singh, S.; Sharma, S.C.; Singh, G.D.; Gupta, V.K.; Gupta, B.D.; Johri, R.K. Anti-allergic effects of herbal product from Allium cepa (bulb). J. Med. Food 2009, 12, 374–382. [CrossRef] 145. Mohammadi-Motlagh, H.R.; Mostafaie, A.; Mansouri, K. Anticancer and anti-inflammatory activities of shallot (Allium ascalonicum) extract. Arch. Med. Sci. 2011, 7, 38–44. [CrossRef] 146. Handbook of Chinese Herbs and Formulas; Yeung, H., Ed.; Institute of Chinese Medicine: London, UK, 1985; Volume 1. 147. Jannat, K.; Rahman, T.; Rahmatullah, M. Traditional uses, phytochemicals and pharmacological properties of Allium tuberosum Rottler ex spreng. J. Med. Plants Stud. 2019, 7, 214–220. 148. Sabha, D.; Hiyasat, B.; Grtzinger, K.; Hennig, L.; Schlegel, F.; Mohr, F.W.; Rauwald, H.W.; Dhein, S. Allium ursinum L.: Bioassayguided isolation and identification of a galactolipid and a phytosterol exerting antiaggregatory effects. Pharmacology 2012, 89, 260–269. [CrossRef] 149. Carotenuto, A.; De Feo, V.; Fattorusso, E.; Lanzotti, V.; Magno, S.; Cicala, C. The flavonoids of Allium ursinum. Phytochemistry 1996, 41, 531–536. [CrossRef] 150. Sobolewska, D.; Podolak, I.; Makowska-Was, ˛ J. Allium ursinum: Botanical, phytochemical and pharmacological overview. Phytochem. Rev. 2015, 14, 81–97. [CrossRef] [PubMed] 151. Ivanova, A.; Mikhova, B.; Najdenski, H.; Tsvetkova, I.; Kostova, I. Chemical composition and antimicrobial activity of wild garlic Allium ursinum of Bulgarian origin. Nat. Prod. Commun. 2009, 4, 1059–1062. [CrossRef] [PubMed] 152. Dong, Y.; Ruan, J.; Ding, Z.; Zhao, W.; Hao, M.; Zhang, Y.; Jiang, H.; Zhang, Y.; Wang, T. molecules Phytochemistry and Comprehensive Chemical Profiling Study of Flavonoids and Phenolic Acids in the Aerial Parts of Allium Mongolicum Regel and Their Intestinal Motility Evaluation. Molecules 2020, 25, 577. [CrossRef] 153. Marefati, N.; Ghorani, V.; Shakeri, F.; Boskabady, M.; Kianian, F.; Rezaee, R.; Boskabady, M.H. A review of anti-inflammatory, antioxidant, and immunomodulatory effects of Allium cepa and its main constituents. Pharm. Biol. 2021, 59, 287–302. [CrossRef] 154. Fossen, T.; Slimestad, R.; Andersen, Ø.M. Anthocyanins with 4′ -glucosidation from red onion, Allium cepa. Phytochemistry 2003, 64, 1367–1374. [CrossRef] 155. Xiao, H.; Parkin, K.L. Isolation and identification of potential cancer chemopreventive agents from methanolic extracts of green onion (Allium cepa). Phytochemistry 2007, 68, 1059–1067. [CrossRef] 156. Fossen, T.; Andersen, Ø.M. Anthocyanins from red onion, Allium cepa, with novel aglycone. Phytochemistry 2003, 62, 1217–1220. [CrossRef] 157. Lanzotti, V.; Romano, A.; Lanzuise, S.; Bonanomi, G.; Scala, F. Antifungal saponins from bulbs of white onion, Allium cepa L. Phytochemistry 2012, 74, 133–139. [CrossRef] 158. Nile, A.; Nile, S.H.; Cespedes-Acuña, C.L.; Oh, J.W. Spiraeoside extracted from red onion skin ameliorates apoptosis and exerts potent antitumor, antioxidant and enzyme inhibitory effects. Food Chem. Toxicol. 2021, 154, 112327. [CrossRef] 159. Nohara, T.; Fujiwara, Y.; El-Aasr, M.; Ikeda, T.; Ono, M.; Nakano, D.; Kinjo, J. Thiolane-type sulfides from garlic, onion, and Welsh onion. J. Nat. Med. 2021, 75, 741–751. [CrossRef] [PubMed] 160. El-Aasr, M.; Fujiwara, Y.; Takeya, M.; Ikeda, T.; Tsukamoto, S.; Ono, M.; Nakano, D.; Okawa, M.; Kinjo, J.; Yoshimitsu, H.; et al. Onionin A from Allium cepa inhibits macrophage activation. J. Nat. Prod. 2010, 73, 1306–1308. [CrossRef] [PubMed] 161. Terahara, N.; Yamaguchi, M.; Honda, T. Malonylated anthocyanins from bulbs of red onion, Allium cepa L. Biosci. Biotechnol. Biochem. 1994, 58, 1324–1325. [CrossRef] 162. Pontin, M.; Bottini, R.; Burba, J.L.; Piccoli, P. Allium sativum produces terpenes with fungistatic properties in response to infection with Sclerotium cepivorum. Phytochemistry 2015, 115, 152–160. [CrossRef] 163. Lanzotti, V.; Barile, E.; Antignani, V.; Bonanomi, G.; Scala, F. Antifungal saponins from bulbs of garlic, Allium sativum L. var. Voghiera. Phytochemistry 2012, 78, 126–134. [CrossRef] [PubMed] 164. Okuyama, T.; Fujita, K.; Shibata, S.; Hoson, M.; Kawada, T.; Masaki, M.; Yamate, N. Effects of Chinese drugs “xiebai” and “dasuan” on human platelet aggregation (Allium bakeri, A. sativum). Planta Med. 1989, 55, 242–244. [CrossRef] 165. Timité, G.; Mitaine-Offer, A.C.; Miyamoto, T.; Tanaka, C.; Mirjolet, J.F.; Duchamp, O.; Lacaille-Dubois, M.A. Structure and cytotoxicity of steroidal glycosides from Allium schoenoprasum. Phytochemistry 2013, 88, 61–66. [CrossRef] 166. Fossen, T.; Slimestad, R.; Øvstedal, D.O.; Andersen, Ø.M. Covalent anthocyanin-flavonol complexes from flowers of chive, Allium schoenoprasum. Phytochemistry 2000, 54, 317–323. [CrossRef] 167. Barile, E.; Bonanomi, G.; Antignani, V.; Zolfaghari, B.; Sajjadi, S.E.; Scala, F.; Lanzotti, V. Saponins from Allium minutiflorum with antifungal activity. Phytochemistry 2007, 68, 596–603. [CrossRef] 168. Carotenuto, A.; Fattorusso, E.; Lanzotti, V.; Magno, S.; De Feo, V.; Cicala, C. The flavonoids of Allium neapolitanum. Phytochemistry 1997, 44, 949–957. [CrossRef] Molecules 2022, 27, 4475 42 of 48 169. Chehri, Z.; Zolfaghari, B.; Sadeghi Dinani, M. Isolation of Cinnamic Acid Derivatives from the Bulbs of Allium tripedale. Adv. Biomed. Res. 2018, 7, 60. [CrossRef] 170. Jan, K.; Michael, K. Cysteine sulfoxides and volatile sulfur compounds from Allium tripedale. J. Agric. Food Chem. 2010, 58, 1129–1137. [CrossRef] 171. Fattorusso, E.; Lanzotti, V.; Taglialatela-Scafati, O.; Cicala, C. The flavonoids of leek, Allium porrum. Phytochemistry 2001, 57, 565–569. [CrossRef] 172. Carotenuto, A.; Fattorusso, E.; Lanzotti, V.; Magno, S. Spirostanol saponins of Allium porrum L. Phytochemistry 1999, 51, 1077–1082. [CrossRef] 173. Peng, J.P.; Yao, X.S.; Tezuka, Y.; Kikuchi, T. Furostanol glycosides from bulbs of Allium chinense. Phytochemistry 1996, 41, 283–285. [CrossRef] 174. Kuroda, M.; Mimaki, Y.; Kameyama, A.; Sashida, Y.; Nikaido, T. Steroidal saponins from Allium chinense and their inhibitory activities on cyclic AMP phosphodiesterase and Na+ /K+ ATPase. Phytochemistry 1995, 40, 1071–1076. [CrossRef] 175. Baba, M.; Ohmura, M.; Kishi, N.; Okada, Y.; Shibata, S.; Peng, J.; Yao, S.S.; Nishino, H.; Okuyama, T. Saponins isolated from Allium chinense G. Don and antitumor-promoting activities of isoliquiritigenin and laxogenin from the same drug. Biol. Pharm. Bull. 2000, 23, 660–662. [CrossRef] 176. Peng, J.; Yao, X.; Kobayashi, H.; Ma, C. Novel furostanol glycosides from Allium macrostemon. Planta Med. 1995, 61, 58–61. [CrossRef] 177. Peng, J.P.; Wu, Y.; Yao, X.S.; Okuyama, T.; Narui, T. Two new steroidal saponins from Allium macrostemon. Yao Xue Xue Bao 1992, 27, 918–922. [PubMed] 178. Peng, J.P.; Wang, X.; Yao, X.S. Studies on two new furostanol glycosides from Allium macrostemon Bunge. Yao Xue Xue Bao 1993, 28, 526–531. 179. Usui, A.; Matsuo, Y.; Tanaka, T.; Ohshima, K.; Fukuda, S.; Mine, T.; Yakashiro, I.; Ishimaru, K. Ferulic acid esters of glucosylglucose from Allium macrostemon Bunge. J. Asian Nat. Prod. Res. 2017, 19, 215–221. [CrossRef] 180. Kawashima, K.; Mimaki, Y.; Sashida, Y. Steroidal saponins from the bulbs of Allium schubertii. Phytochemistry 1993, 32, 1267–1272. [CrossRef] 181. Zou, Z.M.; Yu, D.Q.; Cong, P.Z. A steroidal saponin from the seeds of Allium tuberosum. Phytochemistry 2001, 57, 1219–1222. [CrossRef] 182. Sang, S.; Zou, M.; Xia, Z.; Lao, A.; Chen, Z.; Ho, C.T. New spirostanol saponins from Chinese chives (Allium tuberosum). J. Agric. Food Chem. 2001, 49, 4780–4783. [CrossRef] [PubMed] 183. Sang, S.M.; Zou, M.L.; Zhang, X.W.; Lao, A.N.; Chen, Z.L. Tuberoside M, a new cytotoxic spirostanol saponin from the seeds of Allium tuberosum. J. Asian Nat. Prod. Res. 2002, 4, 67–70. [CrossRef] [PubMed] 184. Mimaki, Y.; Kawashima, K.; Kanmoto, T.; Sashida, Y. Steroidal glycosides from Allium albopilosum and A. ostrowskianum. Phytochemistry 1993, 34, 799–805. [CrossRef] 185. Zolfaghari, B.; Yazdiniapour, Z.; Sadeghi, M.; Akbari, M.; Troiano, R.; Lanzotti, V. Cinnamic acid derivatives from welsh onion (Allium fistulosum) and their antibacterial and cytotoxic activities. Phytochem. Anal. 2021, 32, 84–90. [CrossRef] 186. Sang, S.; Lao, A.; Wang, Y.; Chin, C.K.; Rosen, R.T.; Ho, C.T. Antifungal constituents from the seeds of Allium fistulosum L. J. Agric. Food Chem. 2002, 50, 6318–6321. [CrossRef] 187. Tsuruoka, T.; Ishikawa, K.; Hosoe, T.; Davaajab, D.; Duvjir, S.; Surenjav, U. A new cinnamoylphenethylamine derivative from a Mongolian Allium species, Allium carolinianum. J. Nat. Med. 2018, 72, 332–334. [CrossRef] 188. Zamri, N.; Hamid, H.A. Comparative Study of Onion (Allium cepa) and Leek (Allium ampeloprasum): Identification of Organosulphur Compounds by UPLC-QTOF/MS and Anticancer Effect on MCF-7 Cells. Plant Foods Hum. Nutr. 2019, 74, 525–530. [CrossRef] 189. Kang, L.-P.; Liu, Z.-J.; Zhang, L.; Tan, D.-W.; Zhao, Y.; Zhao, Y.; Chen, H.-B.; Ma, B.-P. New furostanol saponins from Allium ascalonicum L. Magn. Reson. Chem. Magn. Reson. Chem 2007, 45, 725–733. [CrossRef] [PubMed] 190. Kubec, R.; Cody, R.B.; Dane, A.J.; Musah, R.A.; Schraml, J.; Vattekkatte, A.; Block, E. Applications of direct analysis in real time-mass spectrometry (DART-MS) in Allium chemistry. (Z)-butanethial S-oxide and 1-butenyl thiosulfinates and their S-(E)-1butenylcysteine S-oxide precursor from Allium siculum. J. Agric. Food Chem. 2010, 58, 1121–1128. [CrossRef] 191. Hu, X.-P.; Zhou, H.; Du, Y.-M.; Ou, S.-Y.; Yan, R.; Wang, Y. Two new flavonoids from the bark of Allium chrysanthum. J. Asian Nat. Prod. Res. 2017, 19, 229–234. [CrossRef] [PubMed] 192. Kusterer, J.; Vogt, A.; Keusgen, M. Isolation and identification of a new cysteine sulfoxide and volatile sulfur compounds from Allium subgenus Melanocrommyum. J. Agric. Food Chem. 2010, 58, 520–526. [CrossRef] [PubMed] 193. Morita, T.; Ushiroguchi, T.; Hayashi, N.; Matsuura, H.; Itakura, Y.; Fuwa, T. Steroidal saponins from elephant garlic, bulbs of Allium ampeloprasum L. Chem. Pharm. Bull. 1988, 36, 3480–3486. [CrossRef] 194. Lee, K.T.; Choi, J.H.; Kim, D.H.; Son, K.H.; Kim, W.B.; Kwon, S.H.; Park, H.J. Constituents and the antitumor principle of Allium victorialis var. platyphyllum. Arch. Pharm. Res. 2001, 24, 44–50. [CrossRef] 195. Akhov, L.S.; Musienko, M.M.; Piacente, S.; Pizza, C.; Oleszek, W. Structure of steroidal saponins from underground parts of Allium nutans L. J. Agric. Food Chem. 1999, 47, 3193–3196. [CrossRef] 196. Mimaki, Y.; Matsumoto, K.; Sashida, Y.; Nikaido, T.; Ohmoto, T. New steroidal saponins from the bulbs of Allium giganteum exhibiting potent inhibition of cAMP phosphodiesterase activity. Chem. Pharm. Bull. 1994, 42, 710–714. [CrossRef] Molecules 2022, 27, 4475 43 of 48 197. Ren, L.; Yaun-Fei, W.; Qian, S.; Hua-Bin, H. Chemical composition and antimicrobial activity of the essential oil from Allium hookeri consumed in Xishuangbanna, Southwest China. Nat. Prod. Commun. 2014, 9, 863–864. 198. El-Saber Batiha, G.; Magdy Beshbishy, A.; Wasef, L.G.; Elewa, Y.H.A.; Al-Sagan, A.; Abd El-Hack, M.E.; Taha, A.E.; Abd-Elhakim, M.Y.; Prasad Devkota, H. Chemical Constituents and Pharmacological Activities of Garlic (Allium sativum L.): A Review. Nutrients 2020, 12, 872. [CrossRef] 199. Kuda, T.; Iwai, A.; Yano, T. Effect of red pepper Capsicum annuum var. conoides and garlic Allium sativum on plasma lipid levels and cecal microflora in mice fed beef tallow. Food Chem. Toxicol. 2004, 42, 1695–1700. [CrossRef] [PubMed] 200. Wallock-Richards, D.; Doherty, C.J.; Doherty, L.; Clarke, D.J.; Place, M.; Govan, J.R.W.; Campopiano, D.J. Garlic revisited: Antimicrobial activity of allicin-containing garlic extracts against Burkholderia cepacia complex. PLoS ONE 2014, 9, e112726. [CrossRef] [PubMed] 201. Ross, Z.M.; O’Gara, E.A.; Hill, D.J.; Sleightholme, H.V.; Maslin, D.J. Antimicrobial properties of garlic oil against human enteric bacteria: Evaluation of methodologies and comparisons with garlic oil sulfides and garlic powder. Appl. Environ. Microbiol. 2001, 67, 475–480. [CrossRef] [PubMed] 202. Pârvu, M.; Moţ, C.A.; Pârvu, A.E.; Mircea, C.; Stoeber, L.; Roşca-Casian, O.; Ţigu, A.B. Allium sativum Extract Chemical Composition, Antioxidant Activity and Antifungal Effect against Meyerozyma guilliermondii and Rhodotorula mucilaginosa Causing Onychomycosis. Molecules 2019, 24, 3958. [CrossRef] 203. Fufa, B.K. Anti-bacterial and Anti-fungal Properties of Garlic Extract (Allium sativum): A Review. Microbiol. Res. J. Int. 2019, 28, 1–5. [CrossRef] 204. Zhen, H.; Fang, F.; Ye, D.; Shu, S.; Zhou, Y.; Dong, Y.; Nie, X.; Li, G. Experimental study on the action of allitridin against human cytomegalovirus in vitro: Inhibitory effects on immediate-early genes. Antivir. Res. 2006, 72, 68–74. [CrossRef] 205. Danquah, C.A.; Tetteh, M.; Amponsah, I.K.; Mensah, A.Y.; Buabeng, K.O.; Gibbons, S.; Bhakta, S. Investigating ghanaian Allium species for anti-infective and resistance-reversal natural product leads to mitigate multidrug-resistance in tuberculosis. Antibiotics 2021, 10, 902. [CrossRef] 206. Satvati, S.A.R.; Shooriabi, M.; Amin, M.; Shiezadeh, F. Evaluation of the Antimicrobial Activity of Tribulus terrestris, Allium sativum, Salvia officinalis, and Allium hirtifolium Boiss Against Enterococcus faecalis. Int. J. Enteric. Pathog. 2017, 5, 63–67. [CrossRef] 207. Abdel-Hafeez, E.H.; Ahmad, A.K.; Kamal, A.M.; Abdellatif, M.Z.M.; Abdelgelil, N.H. In vivo antiprotozoan effects of garlic (Allium sativum) and ginger (Zingiber officinale) extracts on experimentally infected mice with Blastocystis spp. Parasitol. Res. 2015, 114, 3439–3444. [CrossRef] 208. Gruhlke, M.C.H.; Nicco, C.; Batteux, F.; Slusarenko, A.J. The Effects of Allicin—A Reactive Sulfur Species from Garlic, on a Selection of Mammalian Cell Lines. Antioxidants 2016, 6, 1. [CrossRef] 209. Danquah, C.A.; Kakagianni, E.; Khondkar, P.; Maitra, A.; Rahman, M.; Evangelopoulos, D.; McHugh, T.D.; Stapleton, P.; Malkinson, J.; Bhakta, S.; et al. Analogues of Disulfides from Allium stipitatum Demonstrate Potent Anti-tubercular Activities through Drug Efflux Pump and Biofilm Inhibition. Sci. Rep. 2018, 8, 1150. [CrossRef] [PubMed] 210. Asdaq, S.M.B.; Inamdar, M.N. Pharmacodynamic and Pharmacokinetic Interactions of Propranolol with Garlic (Allium sativum) in Rats. Evid. Based. Complement. Alternat. Med. 2011, 2011, 824042. [CrossRef] [PubMed] 211. Jang, H.-J.; Lee, H.-J.; Yoon, D.-K.; Ji, D.-S.; Kim, J.-H.; Lee, C.-H. Antioxidant and antimicrobial activities of fresh garlic and aged garlic by-products extracted with different solvents. Food Sci. Biotechnol. 2018, 27, 219–225. [CrossRef] [PubMed] 212. Abdel-Daim, M.M.; Shaheen, H.M.; Abushouk, A.I.; Toraih, E.A.; Fawzy, M.S.; Alansari, W.S.; Aleya, L.; Bungau, S. Thymoquinone and diallyl sulfide protect against fipronil-induced oxidative injury in rats. Environ. Sci. Pollut. Res. Int. 2018, 25, 23909–23916. [CrossRef] 213. Putnoky, S.; Caunii, A.; Butnariu, M. Study on the stability and antioxidant effect of the Allium ursinumwatery extract. Chem. Cent. J. 2013, 7, 21. [CrossRef] 214. Asgarpanah, J.; Ghanizadeh, B. Pharmacologic and medicinal properties of Allium hirtifolium Boiss. Afr. J. Pharm. Pharmacol. 2012, 6, 1809–1814. [CrossRef] 215. Ahmad, T.A.; El-Sayed, B.A.; El-Sayed, L.H. Development of immunization trials against Eimeria spp. Trials Vaccinol. 2016, 5, 38–47. [CrossRef] 216. Hobauer, R.; Frass, M.; Gmeiner, B.; Kaye, A.D.; Frost, E.A. Garlic extract (Allium sativum) reduces migration of neutrophils through endothelial cell monolayers. Middle East J. Anaesthesiol. 2000, 15, 649–658. 217. Gu, X.; Wu, H.; Fu, P. Allicin attenuates inflammation and suppresses HLA-B27 protein expression in ankylosing spondylitis mice. Biomed. Res. Int. 2013, 2013, 171573. [CrossRef] 218. Jeong, Y.Y.; Ryu, J.H.; Shin, J.-H.; Kang, M.J.; Kang, J.R.; Han, J.; Kang, D. Comparison of Anti-Oxidant and Anti-Inflammatory Effects between Fresh and Aged Black Garlic Extracts. Molecules 2016, 21, 430. [CrossRef] 219. Jin, P.; Kim, J.-A.; Choi, D.-Y.; Lee, Y.-J.; Jung, H.S.; Hong, J.T. Anti-inflammatory and anti-amyloidogeniceffects of a small molecule, 2,4-bis(p-hydroxyphenyl)-2-butenal in Tg2576 Alzheimer’sdisease mice model. J. Neuroinflammation 2013, 10, 767. [CrossRef] [PubMed] 220. Krejčová, P.; Kučerová, P.; Stafford, G.I.; Jäger, A.K.; Kubec, R. Antiinflammatory and neurological activity of pyrithione and related sulfur-containing pyridine N-oxides from Persian shallot (Allium stipitatum). J. Ethnopharmacol. 2014, 154, 176–182. [CrossRef] [PubMed] Molecules 2022, 27, 4475 44 of 48 221. Karunanidhi, A.; Ghaznavi-Rad, E.; Jeevajothi Nathan, J.; Abba, Y.; van Belkum, A.; Neela, V. Allium stipitatum Extract Exhibits In Vivo Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus and Accelerates Burn Wound Healing in a Full-Thickness Murine Burn Model. Evid. Based Complement. Altern. Med. 2017, 2017, 1914732. [CrossRef] 222. Kim, J.E.; Park, K.M.; Lee, S.Y.; Seo, J.H.; Yoon, I.S.; Bae, C.S.; Yoo, J.C.; Bang, M.A.; Cho, S.S.; Park, D.H. Anti-inflammatory effect of Allium hookeri on carrageenan-induced air pouch mouse model. PLoS ONE 2017, 12, e0190305. [CrossRef] [PubMed] 223. Li, Z.; Le, W.; Cui, Z. A novel therapeutic anticancer property of raw garlic extract via injection but not ingestion. Cell Death Discov. 2018, 4, 108. [CrossRef] [PubMed] 224. Chhabria, S.V.; Akbarsha, M.A.; Li, A.P.; Kharkar, P.S.; Desai, K.B. In situ allicin generation using targeted alliinase delivery for inhibition of MIA PaCa-2 cells via epigenetic changes, oxidative stress and cyclin-dependent kinase inhibitor (CDKI) expression. Apoptosis 2015, 20, 1388–1409. [CrossRef] 225. Fleischauer, A.T.; Arab, L. Garlic and cancer: A critical review of the epidemiologic literature. J. Nutr. 2001, 131, 1032S–1040S. [CrossRef] 226. Piscitelli, S.C.; Burstein, A.H.; Welden, N.; Gallicano, K.D.; Falloon, J. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin. Infect. Dis. 2002, 34, 234–238. [CrossRef] 227. Dall’Acqua, S.; Maggi, F.; Minesso, P.; Salvagno, M.; Papa, F.; Vittori, S.; Innocenti, G. Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae). Fitoterapia 2010, 81, 1208–1212. [CrossRef] 228. Szychowski, K.A.; Rybczyńska-Tkaczyk, K.; Gaweł-B˛eben, K.; Świeca, M.; Karaś, M.; Jakubczyk, A.; Matysiak, M.; Binduga, U.E.; Gmiński, J. Characterization of Active Compounds of Different Garlic (Allium sativum L.) Cultivars. Pol. J. Food Nutr. Sci. 2018, 68, 73–81. [CrossRef] 229. Lu, S.-H.; Wu, J.W.; Liu, H.-L.; Zhao, J.-H.; Liu, K.-T.; Chuang, C.-K.; Lin, H.-Y.; Tsai, W.-B.; Ho, Y. The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies. J. Biomed. Sci. 2011, 18, 8. [CrossRef] [PubMed] 230. Mathew, B.; Biju, R. Neuroprotective effects of garlic a review. Libyan J. Med. 2008, 3, 23–33. [CrossRef] [PubMed] 231. Qidwai, W.; Ashfaq, T. Role of garlic usage in cardiovascular disease prevention: An evidence-based approach. Evid. Based. Complement. Alternat. Med. 2013, 2013, 125649. [CrossRef] [PubMed] 232. Ashraf, R.; Aamir, K.; Shaikh, A.R.; Ahmed, T. Effects of garlic on dyslipidemia in patients with type 2 diabetes mellitus. J. Ayub Med. Coll. Abbottabad 2005, 17, 60–64. 233. Zhai, B.; Zhang, C.; Sheng, Y.; Zhao, C.; He, X.; Xu, W.; Huang, K.; Luo, Y. Hypoglycemic and hypolipidemic effect of S-allylcysteine sulfoxide (alliin) in DIO mice. Sci. Rep. 2018, 8, 3527. [CrossRef] 234. Lee, M.-S.; Kim, I.-H.; Kim, C.-T.; Kim, Y. Reduction of body weight by dietary garlic is associated with an increase in uncoupling protein mRNA expression and activation of AMP-activated protein kinase in diet-induced obese mice. J. Nutr. 2011, 141, 1947–1953. [CrossRef] 235. Sobenin, I.; Andrianova, I.; Ionova, V.; Karagodin, V.; Orekhov, A. Anti-aggregatory and fibrinolytic effects of time-released garlic powder tablets. Med. Heal. Sci. J. 2012, 10, 47–51. [CrossRef] 236. Embuscado, M.E. Bioactives from culinary spices and herbs: A review. J. Food Bioact. 2019, 6. [CrossRef] 237. Mohammadi-rika, A.; Beigi-boroujeni, M.; Rajabzadeh, A.; Zarei, L. Effect of Extract of Allium stipitatum on Excisional Wound Healing in Rats. Iran. J. Vet. Surg. 2021, 16, 5–11. 238. Velten, R.; Erdelen, C.; Gehling, M.; Ghrt, A.; Gondol, D.; Lenz, J.; Loekhoff, O.; Wachendorff, U.; Wendisch, D.; Cripowellin, A. Cripowellin A and B, Novel Type of Amaryllidaceae Alkaloid from Crinum powellii. Tetrahedron Lett. 1998, 39, 1737–1740. [CrossRef] 239. Zvetkova, E.; Wirleitner, B.; Tram, N.T.; Schennach, H.; Fuchs, D. Aqueous extracts of Crinum latifolium and Camellia sinensis show immunomodulatory properties in human peripheral blood mononuclear cells. Sci. Pharm. 2001, 79, 2143–2150. [CrossRef] 240. Ulrich, M.R.; Davies, F.T., Jr.; Koh, Y.C.; Duray, S.A.; Egilla, J.N. Micropropagation of Crinum ‘Ellen Bosanquet’ by tri-scales. Sci. Hortic. 1999, 82, 95–102. [CrossRef] 241. Thi Ngoc Tram, N.; Titorenkova, T.V.; Bankova, V.S.; Handjieva, N.V.; Popov, S.S. Crinum L. (Amaryllidaceae). Fitoterapia 2002, 73, 183–208. [CrossRef] 242. Singh, K.A.; Nayak, M.K.; Jagannadham, M.V.; Dash, D. Thrombolytic along with anti-platelet activity of crinumin, a protein constituent of Crinum asiaticum. Blood Cells. Mol. Dis. 2011, 47, 129–132. [CrossRef] 243. Ghosal, S.; Rao, P.H.; Jaiswal, D.K.; Kumar, Y.; Frahm, A.W. Alkaloids of Crinum pratense. Phytochemistry 2007, 20, 2003–2007. [CrossRef] 244. Yoshisuke, T.; Noriaki, K.; Vijaya, K. The Alkaloidal Constituents of Goda-Manel (Crinum zeylanicum L.), a Sri Lankan Folk Medicine. Chem. Pharm. Bull. 1984, 32, 3023–3027. 245. Nordal, I.; Wahlstrom, R. Studies in the Crinum zeylanicum complex in East Africa. Nord. J. Bot. 1982, 2, 465–473. [CrossRef] 246. Bastida, J.; Peeters, P.; Rubiralta, M.; Naturals, D.D.P.; De Farmficia, F.; Barcelona, U. De Alkaloids from crinum kirkii. Phytochemistry 1995, 40, 1291–1293. [CrossRef] 247. Nair, J.J.; Machocho, A.K.; Campbell, W.E.; Brun, R.; Viladomat, F.; Codina, C.; Bastida, J. Alkaloids from Crinum macowanii. Phytochemistry 2000, 54, 5. [CrossRef] 248. Elgorashi, E.E.; Drewes, S.E.; Staden, J. Van Alkaloids from Crinum bulbispermum. Phytochemistry 1999, 52, 533–536. [CrossRef] Molecules 2022, 27, 4475 45 of 48 249. Tallini, L.R.; Carrasco, A.; Acosta León, K.; Vinueza, D.; Bastida, J.; Oleas, N.H. Alkaloid Profiling and Cholinesterase Inhibitory Potential of Crinum × amabile Donn. (Amaryllidaceae) Collected in Ecuador. Plants 2021, 10, 2686. [CrossRef] [PubMed] 250. Tallini, L.R.; Torras-Claveria, L.; de Borges, W.S.; Kaiser, M.; Viladomat, F.; Zuanazzi, J.A.S.; Bastida, J. N-oxide alkaloids from Crinum amabile (Amaryllidaceae). Molecules 2018, 23, 1277. [CrossRef] [PubMed] 251. Panthong, K.; Ingkaninan, K. Amabiloid A from Crinum × amabile Donn ex Ker Gawl. Nat. Prod. Res. 2021, 35, 3220–3225. [CrossRef] [PubMed] 252. Bordoloi, M.; Kotoky, R.; Mahanta, J.J.; Sarma, T.C.; Kanjilal, P.B. Anti-genotoxic hydrazide from Crinum defixum. Eur. J. Med. Chem. 2009, 44, 2754–2757. [CrossRef] 253. Fennell, C.W.; Elgorashi, E.E.; Van Staden, J. Alkaloid production in Crinum moorei cultures. J. Nat. Prod. 2003, 66, 1524–1526. [CrossRef] 254. Masi, M.; Koirala, M.; Delicato, A.; Di Lecce, R.; Merindol, N.; Ka, S.; Seck, M.; Tuzi, A.; Desgagne-Penix, I.; Calabrò, V.; et al. Isolation and Biological Characterization of Homoisoflavanoids and the Alkylamide N-p-Coumaroyltyramine from Crinum biflorum Rottb., an Amaryllidaceae Species Collected in Senegal. Biomolecules 2021, 11, 1298. [CrossRef] 255. Elgorashi, E.; Drewes, S.E.; Van Staden, J. Alkaloids from Crinum moorei. Phytochemistry 2001, 56, 637–640. [CrossRef] 256. Yu, M.; Wang, B.; Qi, Z.; Xin, G.; Li, W. Response surface method was used to optimize the ultrasonic assisted extraction of flavonoids from Crinum asiaticum. Saudi J. Biol. Sci. 2019, 26, 2079–2084. [CrossRef] 257. Khumkhrong, P.; Piboonprai, K.; Chaichompoo, W.; Pimtong, W.; Khongkow, M.; Namdee, K.; Jantimaporn, A.; Japrung, D.; Asawapirom, U.; Suksamrarn, A.; et al. Crinamine Induces Apoptosis and Inhibits Proliferation, Migration, and Angiogenesis in Cervical Cancer SiHa Cells. Biomolecules 2019, 9, 494. [CrossRef] 258. Sun, Q.; Shen, Y.H.; Tian, J.M.; Tang, J.; Su, J.; Liu, R.H.; Li, H.L.; Xu, X.K.; Zhang, W.D. Chemical constituents of Crinum asiaticum L. var. sinicum Baker and their cytotoxic activities. Chem. Biodivers. 2009, 6, 1751–1757. [CrossRef] 259. Kim, S.C.; Kang, J.; Kim, M.K.; Hyun, J.H.; Boo, H.J.; Park, D.B.; Lee, Y.J.; Yoo, E.S.; Kim, Y.H.; Kim, Y.H.; et al. Promotion effect of norgalanthamine, a component of Crinum asiaticum, on hair growth. Eur. J. Dermatol. 2010, 20, 42–48. [CrossRef] 260. Kogure, N.; Katsuta, N.; Kitajima, M.; Takayama, H. Two new alkaloids from Crinum asiaticum var. sinicum. Chem. Pharm. Bull. 2011, 59, 1545–1548. [CrossRef] [PubMed] 261. Do, K.M.; Shin, M.K.; Kodama, T.; Win, N.N.; Prema, P.; Nguyen, H.M.; Hayakawa, Y.; Morita, H. Flavanols and Flavanes from Crinum asiaticum and their Effects on LPS Signaling Pathway through the Inhibition of NF-κB Activation. Planta Med. 2021. [CrossRef] [PubMed] 262. Yu, M.; Chen, Y.; Liu, Y.; Xu, Y.; Wang, B. Efficient polysaccharides from Crinum asiaticum L.’s structural characterization and anti-tumor effect. Saudi J. Biol. Sci. 2019, 26, 2085–2090. [CrossRef] [PubMed] 263. Endo, Y.; Sugiura, Y.; Funasaki, M.; Kagechika, H.; Ishibashi, M.; Ohsaki, A. Two new alkaloids from Crinum asiaticum var. japonicum. J. Nat. Med. 2019, 73, 648–652. [CrossRef] 264. Min, B.S.; Gao, J.J.; Nakamura, N.; Kim, Y.H.; Hattori, M. Cytotoxic alkaloids and a flavan from the bulbs of Crinum asiaticum var. japonicum. Chem. Pharm. Bull. 2001, 49, 1217–1219. [CrossRef] 265. Kim, Y.H.; Park, E.J.; Park, M.H.; Badarch, U.; Woldemichael, G.M.; Beutler, J.A. Crinamine from Crinum asiaticum var. japonicum inhibits hypoxia inducible factor-1 activity but not activity of hypoxia inducible factor-2. Biol. Pharm. Bull. 2006, 29, 2140–2142. [CrossRef] 266. Machocho, A.K.; Bastida, J.; Codina, C.; Viladomat, F.; Brun, R.; Chhabra, S.C. Augustamine type alkaloids from Crinum kirkii. Phytochemistry 2004, 65, 3143–3149. [CrossRef] 267. Presley, C.C.; Du, Y.; Dalal, S.; Merino, E.F.; Butler, J.H.; Rakotonandrasana, S.; Rasamison, V.E.; Cassera, M.B.; Kingston, D.G.I. Isolation, structure elucidation, and synthesis of antiplasmodial quinolones from Crinum firmifolium. Bioorganic Med. Chem. 2017, 25, 4203–4211. [CrossRef] 268. Chen, M.X.; Huo, J.M.; Hu, J.; Xu, Z.P.; Zhang, X. Amaryllidaceae alkaloids from Crinum latifolium with cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Fitoterapia 2018, 130, 48–53. [CrossRef] 269. Tian, H.; Liu, Q.J.; Wang, J.T.; Zhang, L. Antimicrobial crinane-type alkaloids from the bulbs of Crinum latifolium. J. Asian Nat. Prod. Res. 2021, 23, 1023–1029. [CrossRef] [PubMed] 270. Nam, N.H.; Kim, Y.; You, Y.J.; Hong, D.H.; Kim, H.M.; Ahn, B.Z. New constituents from Crinum latifolium with inhibitory effects against tube-like formation of human umbilical venous endothelial cells. Nat. Prod. Res. 2004, 18, 485–491. [CrossRef] 271. N’Tamon, A.D.; Okpekon, A.T.; Bony, N.F.; Bernadat, G.; Gallard, J.F.; Kouamé, T.; Séon-Méniel, B.; Leblanc, K.; Rharrabti, S.; Mouray, E.; et al. Streamlined targeting of Amaryllidaceae alkaloids from the bulbs of Crinum scillifolium using spectrometric and taxonomically-informed scoring metabolite annotations. Phytochemistry 2020, 179, 112485. [CrossRef] [PubMed] 272. Berkov, S.; Romani, S.; Herrera, M.; Viladomat, F.; Codina, C.; Momekov, G.; Ionkova, I.; Bastida, J. Antiproliferative alkaloids from Crinum zeylanicum. Phytother. Res. 2011, 25, 1686–1692. [CrossRef] [PubMed] 273. Ka, S.; Masi, M.; Merindol, N.; Di Lecce, R.; Plourde, M.B.; Seck, M.; Górecki, M.; Pescitelli, G.; Desgagne-Penix, I.; Evidente, A. Gigantelline, gigantellinine and gigancrinine, cherylline- and crinine-type alkaloids isolated from Crinum jagus with antiacetylcholinesterase activity. Phytochemistry 2020, 175, 112390. [CrossRef] 274. Cortes, N.; Sierra, K.; Alzate, F.; Osorio, E.H.; Osorio, E. Alkaloids of Amaryllidaceae as Inhibitors of Cholinesterases (AChEs and BChEs): An Integrated Bioguided Study. Phytochem. Anal. 2017, 29, 217–227. [CrossRef] Molecules 2022, 27, 4475 46 of 48 275. Abebe, B.; Tadesse, S.; Hymete, A.; Bisrat, D. Antiproliferative Effects of Alkaloids from the Bulbs of Crinum abyscinicum Hochst. ExA. Rich. Evid. Based. Complement. Alternat. Med. 2020, 2020, 2529730. [CrossRef] 276. Presley, C.C.; Krai, P.; Dalal, S.; Su, Q.; Cassera, M.; Goetz, M.; Kingston, D.G.I. New potently bioactive alkaloids from Crinum erubescens. Bioorganic Med. Chem. 2016, 24, 5418–5422. [CrossRef] 277. Abdel-Halim, O.B.; Marzouk, A.M.; Mothana, R.; Awadh, N. A new tyrosinase inhibitor from Crinum yemense as potential treatment for hyperpigmentation. Pharmazie 2008, 63, 405–407. [PubMed] 278. Abdel-Halim, O.B.; Morikawa, T.; Ando, S.; Matsuda, H.; Yoshikawa, M. New crinine-type alkaloids with inhibitory effect on induction of inducible nitric oxide synthase from Crinum yemense. J. Nat. Prod. 2004, 67, 1119–1124. [CrossRef] 279. Aboul-Ela, M.A.; El-Lakany, A.M.; Hammoda, H.M. Alkaloids from the bulbs of Crinum bulbispermum. Pharmazie 2004, 59, 894–896. [CrossRef] [PubMed] 280. Ramadan, M.A.; Kamel, M.S.; Ohtani, K.; Kasai, R.; Yamasaki, K. Minor phenolics from Crinum bulbispermum bulbs. Phytochemistry 2000, 54, 891–896. [CrossRef] 281. Ali, A.; Ramadan, M.; Frahm, A. Alkaloidal Constituents of Crinum bulbispermum III: Bulbispermine—A New Alkaloid of Crinum bulbispermum. Planta Med. 1984, 50, 424–427. [CrossRef] [PubMed] 282. Kissling, J.; Ioset, J.R.; Marston, A.; Hostettmann, K. Bio-guided isolation of cholinesterase inhibitors from the bulbs of Crinum x powellii. Phytother. Res. 2005, 19, 984–987. [CrossRef] 283. Niño, J.; Hincapié, G.M.; Correa, Y.M.; Mosquera, O.M. Alkaloids of Crinum x powellii “Album” (Amaryllidaceae) and their topoisomerase inhibitory activity. Z. Naturforsch. C 2007, 62, 223–226. [CrossRef] [PubMed] 284. Houghton, P.J.; Agbedahunsi, J.M.; Adegbulugbe, A. Choline esterase inhibitory properties of alkaloids from two Nigerian Crinum species. Phytochemistry 2004, 65, 2893–2896. [CrossRef] 285. Nkanwen, E.R.S.; Gatsing, D.; Ngamga, D.; Fodouop, S.P.C.; Tane, P. Antibacterial agents from the leaves of Crinum purpurascens herb (Amaryllidaceae). Afr. Health Sci. 2009, 9, 264–269. [CrossRef] [PubMed] 286. Refaat, J.; Kamel, M.S.; Ramadan, M.A.; Ali, A.A. Crinum; An endless source of bioactive principles: A Review. Part V. Biological Profile. Int. J. Pharm. Sci. Res. 2013, 4, 1239–1252. 287. Mahomoodally, M.F.; Sadeer, N.B.; Suroowan, S.; Jugreet, S.; Lobine, D.; Rengasamy, K.R.R. Ethnomedicinal, phytochemistry, toxicity and pharmacological benefits of poison bulb—Crinum asiaticum L. S. Afr. J. Bot. 2021, 136, 16–29. [CrossRef] 288. Kim, Y.H.; Kim, K.H.; Han, C.S.; Park, S.H.; Yang, H.C.; Lee, B.Y.; Eom, S.-Y.; Kim, Y.-S.; Kim, J.-H.; Lee, N.H. Anti-inflammatory activity of Crinum asiaticum Linne var. japonicum extract and its application as a cosmeceutical ingredient. J. Cosmet. Sci. 2008, 59, 419–430. 289. Samud, A.M.; Asmawi, M.Z.; Sharma, J.N.; Yusof, A.P.M. Anti-inflammatory activity of Crinum asiaticum plant and its effect on bradykinin-induced contractions on isolated uterus. Immunopharmacology 1999, 43, 311–316. [CrossRef] 290. Rahman, A.S.M.; Azad, H.; Nazim, U.A. Analgesic and anti-inflammatory effects of Crinum asiaticum leaf alcoholic extract in animal models. Afr. J. Biotechnol. 2013, 12, 212–218. [CrossRef] 291. Minkah, P.A.B.; Danquah, C.A. Anti-infective, anti-inflammatory and antipyretic activities of the bulb extracts of Crinum jagus (J. Thomps.) Dandy (Amaryllidaceae). Sci. Afr. 2021, 12, e00723. [CrossRef] 292. Ratnasooriya, W.D.; Deraniyagala, S.A.; Bathige, S.D.N.K.; Hettiarachchi, H.D.I. Leaf extract of Crinum bulbispermum has antinociceptive activity in rats. J. Ethnopharmacol. 2005, 97, 123–128. [CrossRef] [PubMed] 293. Ahmad, B. Chemical composition and antifungal, phytotoxic, brine shrimp cytotoxicity, insecticidal and antibacterial activities of the essential oils of Acacia modesta. J. Med. Plants Res. 2012, 6, 4653–4659. [CrossRef] 294. Alawode, T.T.; Lajide, L.; Owolabi, B.J.; Olaleye, M.T. Evaluation of Extracts of Leaves of Crinum jagus for Antimicrobial Properties. J. Appl. Sci. Environ. Manag. 2020, 24, 1197–1201. [CrossRef] 295. Nguyen, H.M.; Nguyen, N.Y.T.; Chau, N.T.N.; Nguyen, A.B.T.; Tran, V.K.T.; Hoang, V.; Le, T.M.; Wang, H.C.; Yen, C.H. Bioassayguided discovery of potential partial extracts with cytotoxic effects on liver cancer cells from vietnamese medicinal herbs. Processes 2021, 9, 1956. [CrossRef] 296. Mannan, A.; Kawser, M.J.; Ahmed, A.M.A.; Islam, N.N.; Alam, S.M.M.; Emon, M.A.E.K.; Gupta, S. Das Assessment of antibacterial, thrombolytic and cytotoxic potential of cassia alata seed oil. J. Appl. Pharm. Sci. 2011, 1, 56–59. 297. Yui, S.; Mikami, M.; Kitahara, M.; Yamazaki, M. The inhibitory effect of lycorine on tumor cell apoptosis induced by polymorphonuclear leukocyte-derived calprotectin. Immunopharmacology 1998, 40, 151–162. [CrossRef] 298. Patel, D. Crinum asiaticum Linn: A Medicinal Herb as Well as Ornamental Plant in Central India. Int. J. Environ. Sci. Nat. Resour. 2017, 6, 1–7. [CrossRef] 299. Hyun, J.H.; Kang, J.; Kim, S.C.; Kim, E.; Kang, J.H.; Kwon, J.M.; Park, D.B.; Lee, Y.J.; Yoo, E.S.; Kang, H.K. The effects of crinum asiaticum on the apoptosis induction and the reversal of multidrug resistance in hl-60/mx2. Toxicol. Res. 2008, 24, 29–36. [CrossRef] [PubMed] 300. Yusoff, S.M. Anti-angiogenesis as a possible mechanism of action for anti-tumor (potential anti-cancer) activity of Crinum asiaticum leaf methanol extract. J. Angiother. 2017, 1, E012–E017. [CrossRef] 301. Tan, W.-N.; Shahbudin, F.N.; Mohamed Kamal, N.N.S.N.; Tong, W.-Y.; Leong, C.-R.; Lim, J.-W. Volatile Constituents of the Leaf Essential Oil of Crinum asiaticum and their Antimicrobial and Cytotoxic Activities. J. Essent. Oil Bear. Plants 2019, 22, 947–954. [CrossRef] Molecules 2022, 27, 4475 47 of 48 302. Lim, H.S.; Kim, Y.; Kim, Y.J.; Sohn, E.; Kim, J.H.; Jeong, S.J. The Effects of Crinum asiaticum var. japonicum Baker Seeds on Neuroprotection and Antineuroinflammation in Neuronal Cell Lines. Nat. Prod. Commun. 2020, 15, 10. [CrossRef] 303. Seoposengwe, K.; van Tonder, J.J.; Steenkamp, V. In vitro neuroprotective potential of four medicinal plants against rotenoneinduced toxicity in SH-SY5Y neuroblastoma cells. BMC Complement. Altern. Med. 2013, 13, 353. [CrossRef] [PubMed] 304. Ofori, M.; Danquah, C.A.; Ativui, S.; Doe, P.; Asamoah, W.A. In-Vitro Anti-Tuberculosis, Anti-Efflux Pumps and Anti-Biofilm Effects of Crinum Asiaticum Bulbs. Biomed. Pharmacol. J. 2021, 14, 1905–1915. [CrossRef] 305. Goswami, S.; Das, R.; Ghosh, P.; Chakraborty, T.; Barman, A.; Ray, S. Comparative antioxidant and antimicrobial potentials of leaf successive extract fractions of poison bulb, Crinum asiaticum L. Ind. Crops Prod. 2020, 154, 112667. [CrossRef] 306. Fu, L.; Zheng, Y.; Zhang, P.; Zhang, H.; Xu, Y.; Zhou, J.; Zhang, H.; Karimi-Maleh, H.; Lai, G.; Zhao, S.; et al. Development of an electrochemical biosensor for phylogenetic analysis of Amaryllidaceae based on the enhanced electrochemical fingerprint recorded from plant tissue. Biosens. Bioelectron. 2020, 159, 112212. [CrossRef] 307. Min, B.S.; Kim, Y.H.; Tomiyama, M.; Nakamura, N.; Miyashiro, H.; Otake, T.; Hattori, M. Inhibitory effects of Korean plants on HIV-1 activities. Phytother. Res. 2001, 15, 481–486. [CrossRef] 308. Naira, J.J.; Van Staden, J.; Bonnet, S.L.; Wilhelm, A. Antibacterial properties of the family amaryllidaceae: Evaluation of plant extracts in vitro. Nat. Prod. Commun. 2017, 12, 1145–1151. [CrossRef] 309. Surain, P.; Aneja, K.R. Anticandidal potential of Crinum asiaticum leaves extract against selected oral and vaginal Candida pathogens. J. Innov. Biol. 2014, 6473, 27–30. 310. Noubissi, P.A.; Fokam Tagne, M.A.; Fankem, G.O.; Ngakou Mukam, J.; Wambe, H.; Kamgang, R. Effects of Crinum jagus Water/Ethanol Extract on Shigella flexneri-Induced Diarrhea in Rats. Evid. -Based Complement. Altern. Med. 2019, 2019, 9537603. [CrossRef] [PubMed] 311. Udegbunam, S.O.; Udegbunam, R.I.; Nnaji, T.O.; Anyanwu, M.U.; Kene, R.O.C.; Anika, S.M. Antimicrobial and antioxidant effect of methanolic Crinum jagus bulb extract in wound healing. J. Intercult. Ethnopharmacol. 2015, 4, 239–248. [CrossRef] [PubMed] 312. Azikiwe, C.; Amazu, L. The potential organo-toxicity safety of Morpholine and Crinum jagus in rats. Discovery 2015, 10, 113–120. 313. Akintola, A.O.; Kehinde, A.O.; Adebiyi, O.E.; Ademowo, O.G. Anti-tuberculosis activities of the crude methanolic extract and purified fractions of the bulb of Crinum jagus. Niger. J. Physiol. Sci. 2013, 28, 135–140. 314. Ka, S.; Merindol, N.; Sow, A.A.; Singh, A.; Landelouci, K.; Plourde, M.B.; Pépin, G.; Masi, M.; Di Lecce, R.; Evidente, A.; et al. Amaryllidaceae Alkaloid Cherylline Inhibits the Replication of Dengue and Zika Viruses. Antimicrob. Agents Chemother. 2021, 65, e0039821. [CrossRef] 315. Maroyi, A. A review of ethnoboatany, therapeutic value, phytochemistry and pharmacology of Crinum macowanii Baker: A highly traded bulbous plant in Southern Africa. J. Ethnopharmacol. 2016, 194, 595–608. [CrossRef] 316. Ilavenil, S.; Kaleeswaran, B.; Sumitha, P.; Tamilvendan, D.; Ravikumar, S. Protection of human erythrocyte using Crinum asiaticum extract and lycorine from oxidative damage induced by 2-amidinopropane. Saudi J. Biol. Sci. 2011, 18, 181–187. [CrossRef] 317. Uddin, Z.; Bin, T.; Kumar, A.; Jenny, A.; Dutta, M.; Morshed, M.; Kawsar, H. Anti-Inflammatory and Antioxidant Activity of Leaf extract of Crinum asiaticum. J. Pharm. Res. 2015, 5, 5553–5556. 318. Indradevi, S.; Ilavenil, S.; Kaleeswaran, B.; Srigopalram, S.; Ravikumar, S. Ethanolic extract of Crinum asiaticum attenuates hyperglycemia-mediated oxidative stress and protects hepatocytes in alloxan induced experimental diabetic rats. J. King Saud. Univ. Sci. 2015, 24, 171–177. [CrossRef] 319. Ghane, S.G.; Attar, U.A.; Yadav, P.B.; Lekhak, M.M. Antioxidant, anti-diabetic, acetylcholinesterase inhibitory potential and estimation of alkaloids (lycorine and galanthamine) from Crinum species: An important source of anticancer and anti-Alzheimer drug. Ind. Crops Prod. 2018, 125, 168–177. [CrossRef] 320. Alawode, T.T.; Lajide, L.; Owolabi, B.J.; Olaleye, M.T. Studies on In vitro Antioxidant and Anti-Inflammatory Activities of Crinum jagus Leaves and Bulb Extracts. Int. J. Biochem. Res. Rev. 2019, 28, 1–9. [CrossRef] 321. Adewusi, E.A.; Steenkamp, V. In vitro screening for acetylcholinesterase inhibition and antioxidant activity of medicinal plants from southern Africa. Asian Pac. J. Trop. Med. 2011, 4, 829–835. [CrossRef] 322. Chahal, S.; Lekhak, M.M.; Kaur, H.; Shekhawat, M. Unraveling the medicinal potential and conservation of Indian Crinum Unraveling the medicinal potential and conservation of Indian Crinum (Amaryllidaceae) species. S. Afr. J. Bot. 2020, 136, 7–15. [CrossRef] 323. Kang, J.; Choi, J.H.; Lee, J.G.; Yoo, E. The Mechanism of Crinum asiaticum var. japonicum on the Activation of Anagen. Korean J. Pharmacogn. 2017, 48, 148–154. 324. Jeong, Y.J.; Sohn, E.H.; Jung, Y.H.; Yoon, W.J.; Cho, Y.M.; Kim, I.; Lee, S.R.; Kang, S.C. Anti-obesity effect of Crinum asiaticum var. japonicum Baker extract in high-fat diet-induced and monogenic obese mice. Biomed. Pharmacother. 2016, 82, 35–43. [CrossRef] 325. Taiwe, G.S.; Tchoya, T.B.; Menanga, J.R.; Dabole, B.; De Waard, M. Anticonvulsant activity of an active fraction extracted from Crinum jagus L. (Amaryllidaceae), and its possible effects on fully kindled seizures, depression-like behaviour and oxidative stress in experimental rodent models. J. Ethnopharmacol. 2016, 194, 421–433. [CrossRef] 326. Heinrich, M. Galanthamine from Galanthus and other Amaryllidaceae–chemistry and biology based on traditional use. Alkaloids. Chem. Biol. 2010, 68, 157–165. [CrossRef] 327. Jilani, M.S.; Tagwireyi, D.; Gadaga, L.L.; Maponga, C.C.; Mutsimhu, C. Cognitive-Enhancing Effect of a Hydroethanolic Extract of Crinum macowanii against Memory Impairment Induced by Aluminum Chloride in BALB/c Mice. Behav. Neurol. 2018, 2018, 2057219. [CrossRef] Molecules 2022, 27, 4475 48 of 48 328. Snijman, D.A.; Meerow, A.W. Floral and macroecological evolution within Cyrtanthus (Amaryllidaceae): Inferences from combined analyses of plastid ndhF and nrDNA ITS sequences. S. Afr. J. Bot. 2010, 76, 217–238. [CrossRef] 329. Galley, C.; Bytebier, B.; Bellstedt, D.U.; Linder, H.P. The Cape element in the Afrotemperate flora: From Cape to Cairo? Proc. R. Soc. B Biol. Sci. 2007, 274, 535–543. [CrossRef] 330. Mucina, L.; Rutherford, M.C. The Vegetation of South Africa, Lesotho and Swaziland; South African National Biodiversity Institute: Cape Town, South Africa, 2006. 331. Born, J.; Linder, H.P.; Desmet, P. The Greater Cape Floristic Region. J. Biogeogr. 2007, 34, 147–162. [CrossRef] 332. Cowling, R.M.; Procheş, Ş.; Vlok, J.H.J. On the origin of southern African subtropical thicket vegetation. S. Afr. J. Bot. 2005, 71, 1–23. [CrossRef] 333. Bhat, R.B.; Jacobs, T.V. Traditional herbal medicine in Transkei. J. Ethnopharmacol. 1995, 48, 7–12. [CrossRef] 334. Nwude, N.; Ebong, O.O. Some plants used in the treatment of leprosy in Africa. Lepr. Rev. 1980, 51, 11–18. [CrossRef] 335. Rárová, L.; Ncube, B.; Van Staden, J.; Fürst, R.; Strnad, M.; Gruz, J. Identification of Narciclasine as an in Vitro Anti-Inflammatory Component of Cyrtanthus contractus by Correlation-Based Metabolomics. J. Nat. Prod. 2019, 82, 1372–1376. [CrossRef] 336. Hutchings, A.; Scott, A.H.; University of Zululand; National Botanical Institute (South Africa). Zulu Medicinal Plants: An Inventory; University of Natal Press: Scottsville, South Africa, 1996; ISBN 0869808931. 337. Nair, J.J.; Bastida, J.; Codina, C.; Viladomat, F.; Van Staden, J. Alkaloids of the South African amaryllidaceae: A review. Nat. Prod. Commun. 2013, 8, 1335–1350. [CrossRef] 338. Mahlangeni, N.T.; Moodley, R.; Jonnalagadda, S.B. Phytochemical analysis of Cyrtanthus obliquus bulbs from the informal street market of Kwazulu-Natal, South Africa. Afr. J. Tradit. Complement. Altern. Med. 2015, 12, 28–34. [CrossRef] 339. Brine, N.D.; Campbell, W.E.; Bastida, J.; Herrera, M.R.; Viladomat, F.; Codina, C.; Smith, P.J. A dinitrogenous alkaloid from Cyrtanthus obliquus. Phytochemistry 2002, 61, 443–447. [CrossRef] 340. Masi, M.; Mubaiwa, B.; Mabank, T.; Karakoyun; Cimmino, A.; Van Otterlo, W.A.L.; Green, I.R.; Evidente, A. Alkaloids isolated from indigenous South African Amaryllidaceae: Crinum buphanoides (Welw. ex Baker), Crinum graminicola (I. Verd.), Cyrtanthus mackenii (Hook. f) and Brunsvigia grandiflora (Lindl). S. Afr. J. Bot. 2018, 118, 188–191. [CrossRef] 341. Elgorashi, E.E.; Van Staden, J. Pharmacological screening of six Amaryllidaceae species. J. Ethnopharmacol. 2004, 90, 27–32. [CrossRef] [PubMed] 342. Elgorashi, E.E.; Van Staden, J. Alkaloids from Cyrtanthus falcatus. S. Afr. J. Bot. 2003, 69, 593–594. [CrossRef] 343. Weniger, B.; Italiano, L.; Beck, J.P.; Bastida, J.; Bergonon, S.; Codina, C.; Lobstein, A.; Anton, R. Cytotoxic activity of Amaryllidaceae alkaloids. Planta Med. 1995, 61, 77–79. [CrossRef] [PubMed] 344. Elgorashi, E.E.; Stafford, G.I.; Mulholland, D.; Van Staden, J. Isolation of captan from Cyrtanthus suaveolens: The effect of pesticides on the quality and safety of traditional medicine. S. Afr. J. Bot. 2004, 70, 512–514. [CrossRef] 345. Kim, H.W.; Wang, M.; Leber, C.A.; Nothias, L.F.; Reher, R.; Kang, K.B.; van der Hooft, J.J.J.; Dorrestein, P.C.; Gerwick, W.H.; Cottrell, G.W. NPClassifier: A Deep Neural Network-Based Structural Classification Tool for Natural Products. J. Nat. Prod. 2021, 84, 2795–2807. [CrossRef] [PubMed]

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