plants
Review
The Genus Lagochilus (Lamiaceae): A Review of Its Diversity,
Ethnobotany, Phytochemistry, and Pharmacology
Nilufar Z. Mamadalieva 1,2, * , Davlat Kh. Akramov 1 , Ludger A. Wessjohann 2 , Hidayat Hussain 2 ,
Chunlin Long 3,4 , Komiljon Sh. Tojibaev 5 , Elham Alshammari 6 , Mohamed L. Ashour 7,8
and Michael Wink 9, *
1
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Citation: Mamadalieva, N.Z.;
Akramov, D.K.; Wessjohann, L.A.;
Hussain, H.; Long, C.; Tojibaev, K.S.;
Alshammari, E.; Ashour, M.L.; Wink,
M. The Genus Lagochilus (Lamiaceae):
A Review of Its Diversity,
Ethnobotany, Phytochemistry, and
Pharmacology. Plants 2021, 10, 132.
https://doi.org/10.3390/
plants10010132
Received: 26 November 2020
Accepted: 8 January 2021
Published: 11 January 2021
Publisher’s Note: MDPI stays neutral with regard to jurisdictional clai-
*
Institute of the Chemistry of Plant Substances of the Academy Sciences of Uzbekistan, Mirzo Ulugbek Str 77,
Tashkent 100170, Uzbekistan; a.davlat@inbox.ru
Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale),
Germany; ludger.wessjohann@ipb-halle.de (L.A.W.); hidayat.hussain@ipb-halle.de (H.H.)
College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China;
long@mail.kib.ac.cn
Key Laboratory of Ethnomedicine, Ministry of Education, Minzu University of China, Beijing 100081, China
Institute of Botany of the Academy Sciences of Uzbekistan, Durmon Yuli Str 32, Tashkent 100125, Uzbekistan;
ktojibaev@mail.ru
Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University,
Riyadh 11671, Saudi Arabia; ejalshammari@pnu.edu.sa
Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College,
Jeddah 21442, Saudi Arabia; ashour@pharma.asu.edu.eg
Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
Department of Pharmaceutical Biology, Institute of Pharmacy and Molecular Biotechnology,
Heidelberg University, 69120 Heidelberg, Germany
Correspondence: nmamadalieva@yahoo.com (N.Z.M.); wink@uni-heidelberg.de (M.W.);
Tel.: +49-6221-54-4880 (M.W.); Fax: +49-6221-54-4884 (M.W.)
Abstract: The genus Lagochilus (Lamiaceae) is native to Central, South-Central, and Eastern Asia. It
comprises 44 species, which have been commonly used as herbal medicines for the treatments of
various ailments for thousands of years, especially in Asian countries. This review aims to summarize
the chemical constituents and pharmacological activities of species from the genus Lagochilus to
unveil opportunities for future research. In addition, we provide some information about their
traditional uses, botany, and diversity. More than 150 secondary metabolites have been reported from
Lagochilus, including diterpenes, flavonoids, phenolic compounds, triterpenoids, iridoid glycosides,
lignans, steroids, alkaloids, polysaccharides, volatile, non-volatile and aromatic compounds, lipids,
carbohydrates, minerals, vitamins, and other secondary metabolites. In vitro and in vivo pharmacological studies on the crude extracts, fractions, and isolated compounds from Lagochilus species
showed hemostatic, antibacterial, anti-inflammatory, anti-allergic, cytotoxic, enzyme inhibitory,
antispasmodic, hypotensive, sedative, psychoactive, and other activities.
Keywords: Lagochilus; Lamiaceae; diversity; traditional medicine; phytochemistry; secondary
metabolites; pharmacology; biological properties
ms in published maps and institutional affiliations.
1. Introduction
Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Terrestrial plants have been used for centuries as an endless well for supplying
many medicinally important secondary metabolites that are used effectively in curing
various ailments. They are considered as the milestone of all the traditional medicinal
systems used throughout the whole world since antiquity. This fact attracted researchers in
drug discovery to explore these plants frequently with the aim of finding new secondary
metabolites or to validate the claimed ethnopharmacological uses.
Family Lamiaceae (the mint family) is among the largest family that contains about
236 genera and 6900 to 7200 species. The family is famous for many of its widely used
Plants 2021, 10, 132. https://doi.org/10.3390/plants10010132
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genera including Salvia, Scutellaria, Stachys, Plectranthus, Hyptis, Teucrium, Vitex, Thymus,
and Nepeta. Members from the Lamiaceae are important ornamental, medicinal, and
aromatic plants and have been used as traditional herbal medicines for thousands of
years [1]. They are also used as culinary herbs, spices, and vegetables and as ingredients in
cosmetics, hygienic products, and perfumes [2].
The genus Lagochilus is a small genus that comprises about 44 species that are native
to Central, South-Central, and Eastern Asia [3,4]. It is highly drought-tolerant and is
considered a typical mountain plant. Most of these species have been commonly used as
herbal medicines for the treatment of various ailments for thousands of years, especially
in Asian countries. Species of this genus exhibit various pharmacological effects, such as
hemostatic, antispasmodic, and anti-edemic properties, and can be used against bleeding,
coronary heart disease, chest pain, skin conditions, stomach pain, and as a tranquilizer.
The most reported properties include relaxation, insomnia, dementia, euphoria, and subtle
perceptual changes. Lagochilus is also used for the treatment of allergies and skin diseases [5–9]. Pharmacological studies indicated that mainly diterpenoids have hemostatic
abilities [10,11].
Previous chemical instigations on the genus are limited due to the fact that many
species are classified endangered, and the collection of these plants is not easy. However,
this effort on the chemical profiling of the plants belonging to the genus led to the isolation
and characterization of many diterpenes, flavonoids, iridoids, triterpenes, and polysaccharides. The diterpene lagochiline and its derivatives are among the promising hemostatic
agents [5,7,10,11].
To the best of our knowledge, no reviews in the literature provide comprehensive
insights into the medicinal uses and importance of Lagochilus plants. Although there is
some work done about limited species that showed the very promising potential of the
studied plants nevertheless, many other species of the genus remain untouched. Therefore,
this review presented an effort to summarize all the up-to-date published data about
the genus and provided comprehensive and condensed references dealing with all the
required data about botanic characterization, distribution, traditional uses, primary and
secondary metabolites, and pharmacological activities of the undiscovered genus Lagochilus.
This review might shed light on the unseen genus that might attract researchers in drug
discovery to find new compounds with promising biological potential.
2. Materials and Methods
The literature for this review was collected by searching various scientific electronic databases, including GoogleScholar (https://scholar.google.com/), PubMed (https:
//pubmed.ncbi.nlm.nih.gov/), SpringerLink (https://link.springer.com), SciFinder (https:
//scifinder.cas.org/), ScienceDirect (https://www.sciencedirect.com/), and Web of Science (https://mjl.clarivate.com), via searching of these keywords: “Lagochilus and phytochemistry”, “Lagochilus and chemical compounds”, “Lagochilus and traditional uses”,
and “Lagochilus and biological activity” in literature written in English, Russian, and
Uzbek. Additional knowledge from other sources of literature was extracted (books, thesis).
Altogether, about 94 references covering the isolation of phytoconstituents, as well as
the diversity, traditional uses, and biological properties of the Lagochilus genus species
from 1954 to 2020, were chosen unbiased to be reviewed in the work. The Plant List
(http://www.theplantlist.org/), International Plant Name Index (https://ipni.org/), and
Kew Botanical Garden Plant name (https://wcsp.science.kew.org/home.do) databases
were used to validate the scientific name.
The review is built on giving the general botanical characteristics of the genus, followed by distribution of the species worldwide and a compilation of the traditional uses.
Then the chemical isolated secondary metabolites are reported in subclasses based on their
chemical structures, and finally, the biological work was subcategorized based on uses.
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3. Taxonomy and Botany
Within the Lamiaceae family, Lagochilus belongs to the subfamily Lamioideae and
tribe Leonureae Dumort [12]. Species of Lagochilus are subshrubs or perennial herbs
(Figure 1). Rootstocks are woody. Stems are green-white, rigid, and sparsely hirsute. The
leaf blade is rhombic, palmatipartite, or pinnatipartite, with lobes spinescent, sometimes
subtending sterile spinescent bracteoles. Normally, 2–10 flowers grow vertically. The
calyx is campanulate to tubular-campanulate, 5-veined; throat oblique, straight; teeth five,
subequal or three posterior teeth longer, triangular to oblong or broadly ovate, usually
longer than the tube, apex spinescent. Corolla is villous outside, pilose annulate inside,
2-lipped; upper lip oblong, straight, slightly concave, 2-lobed or 4-toothed; lower lip
obliquely spreading, 3-lobed; middle lobe largest, obcordate, 2-lobulate; lateral lobes
straight, acute, or emarginate. Stamens are four, exserted or sub included, anterior two
longer; with filaments complanate; anther cells two, parallel or divergent, ciliate. Style
is filiform, apex subequally 2-cleft. Nutlets are flattened-obconical, oblong–obovoid or
oblong–ovoid, apex truncate or rounded, glandular, dusty hairy, scaly, or glabrous, smooth.
Figure 1. Photograph for some Lagochilus species from Uzbekistan Flora (A): L. inebrians Bunge, (B): L. nevskii Knorring,
(C): L. occultiflorus Rupr., (D): L. olgae Kamelin, (E): L. platycalyx Schrenk, (F): L. proskorjakovii Ikramov, (G): L. seravschanicus
Knorring, (H): L. setulosus Vved., (I): L. vvedenskyi R. Kam. (Photos A, B, D, G are taken by Natalya Beshko, photos C, H are
taken by Alim Gaziev, photo E is taken by Tulkin Tillaev, photos F, I are taken by Akbar Akhmedov).
4. Diversity
The genus Lagochilus is mostly distributed on dry slopes, in valleys, and deserts
from Iran to Mongolia, Russia (south Siberia), northwest China, north Pakistan [1] and
has a distributional center in Tianshan Mountains and Central Asia. The results of the
studies of Zhang et al. [3] showed that the Tianshan Mountains, especially the western
Ili-Kirghizia Tianshan, as well as Sunggar and Kaschgar, were the ancestral area. The
ancestral biome was mainly in the montane steppe zone of valley and slope at altitudes
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of 1700 ± 2700 m above sea level, and the montane desert zone of foothill and fronthill at 800 ± 1700 m. The main center of diversity lies in Central Asia. According to
Tskervanik [12], in world flora, there are 44 species that can be distinguished in Lagochilus.
According to the taxonomy of this author, 34 species grow in the territory of the CIS
(Commonwealth of Independent States).
In the flora of Uzbekistan, this genus is represented by 18 species (Table 1) [13]. Taxa
of the genus Lagochilus basically occur throughout the territory of Uzbekistan, starting from
the deserts to Tian-Shan and Pamir-Alay mountain systems. The majority of species can be
found in the Pamir-Alai Mountain, south-west of Tian-Shan and Turanian lowland [13].
Species from the genus Lagochilus belong to the most vulnerable plant species from the
Lamiaceae family. Out of the existing 18 Lagochilus species in the flora of Uzbekistan, four
are included in the Red Book of the Republic of Uzbekistan [14]: L. vvedenskyi, L. olgae,
L. proskorjakovii, and L. inebrians. The main population of these species grows in Nuratau
and Kyzylkum deserts. On the basis of occurrence, these Red List plant species belong to
category I (disappearing) and II (rare species). In addition, the natural distribution of other
species from this genus, such as L. gypsaceus and L. acutilobus, are also limited across the
country [15]. In the territory of South Kazakhstan, 10 species of Lagochilus were found, and
the areas of these species are located in Karatau, Karzhantau, and Aksu-Zhabagly [16]. In
the Flora of China, there are 14 Lagochilus species distributed wildly in the northwest region.
One of the species, L. ilicifolius, grows in the desert (sandy land) and steppe in northwestern
China (Neimeng, Gansu, Shanxi, and Ningxia provinces), whereas the other 13 species
are distributed mainly in the Xinjiang region [3,10,17]. The Flora of Iran comprises six
species, and four of them (L. macranthus Fisch and C.A. Mey., L. quadridentatus Jamzad,
L. lasiocalyx (Stapf) Jamzad, and L. aucheri Boiss.) are endemic to Iran [4,18,19]. Three species
of Lagochilus are found in Mongolian flora, and they are widely distributed in the Khangai,
Mongolian Altai, Middle Khalkha, Depression of Great Lakes, Valley of Lakes, East Gobi,
Gobi-Altai, Transaltai Gobi, Alashan Gobi regions (Table 1) [20,21].
Table 1. Diversity and distribution of different Lagochilus species in Asia.
Distribution
Region
Afghanistan
western Himalaya
China
northwestern China,
Xinjiang region (Ili Valley,
the Karakoram and
Altai Mountains)
Iran
Kazakhstan
Karatau, Karzhantau,
Aksu-Zhabagly
Species
Reference
L. cabulicus Benth., L. cuneatus Benth., L. hindukushi
Kamelin and Gubanov, L. schugnanicus Knorring
L. ilicifolius Bunge ex Benth., L. grandiflorus C. Y.
Wu and Hsuan, L. platyacanthus Rupr.,
L. kaschgaricus Ruprecht, L. diacanthophyllus (Pall.)
Benth, L. hirtus Fisch. and C.A. Mey., L. bungei
Benth., L. macrodontus Knorring, L. kaschgaricus
Rupr., L. lanatonodus C.Y. Wu and S.J. Hsuan,
L. leiacanthus Fisch. and C.A. Mey., L. pungens
Schrenk, L. xianjiangensis G.J. Liu
L. alutaceus Bunge., L. cabulicus Benth.,
L. macranthus Fisch and C.A. Mey.,
L. quadridentatus Jamzad, L. lasiocalyx (Stapf)
Jamzad, L. aucheri Boiss.
L. acutilobus (Ledeb.) Fisch. and C.A. Mey.,
L. bungei Benth., L. longidentatus Knorr., L. pulcher
Knorr., L. taucumensis Zucker., L. inebrians Bunge,
L. androsswii Knorr., L. leiacanthus Fisch. et Mey,
L. pungens Schrenk, L. hirtus Fisch. et Mey,
L. diacanthophillus Benth., L. kaschgaricus Rupr.,
L. knorringianus Pavlov, L. occultiflorus Rupr.,
L. platyacanthus Rupr., L. platycalyx Schrenk ex
Fisch. and C.A. Mey, L. seravschanicus Knorring,
L. setulosus Vved., L. subhispidus Knorring
https:
//wcsp.science.kew.org/
[3,10,17] https:
//wcsp.science.kew.org/
[4,18,19]
[16]
https:
//wcsp.science.kew.org/
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Table 1. Cont.
Distribution
Region
Species
Reference
Kyrgyzstan
Tian-Shan and Pamir
Alai Mountains
L. diacanthophyllus (Pall.) Benth, L. drobovii Kamelin
and Tzukerv., L. hirsutissimus Vved, L. kaschgaricus
Rupr., L. knorringianus Pavlov, L. occultiflorus Rupr.,
L. paulsenii Briq., L. platyacanthus Rupr.,
L. platycalyx Schrenk ex Fisch. and C.A. Mey,
L. pubescens Vved., L. pulcher Knorring,
L. schugnanicus Knorring, L. turkestanicus Knorring
https:
//wcsp.science.kew.org/
Mongolia
Mongolian Altai and
Khangai Mountains,
Gobi regions
L. bungei Benth., L. diacanthophyllus, L. ilicifolius Bge
[20,21]
Pakistan
Western Pakistan
https:
//wcsp.science.kew.org/
Tajikistan
Pamir-Alay Mountains
L. cabulicus Benth., L. cuneatus Benth.,
L. schugnanicus Knorring
L. botschantzevii Kamelin and Tzukerv., L. gypsaceus
Vved., L. hirsutissimus Vved, L. inebrians Bunge,
L. knorringianus Pavlov, L. kschtutensis Knorring,
L. nevskii Knorring, L. paulsenii Briq.,
L. platyacanthus Rupr, L. platycalyx Schrenk ex Fisch.
and C.A. Mey, L. pubescens Vved, L. schugnanicus
Knorring, L. seravschanicus Knorring,
L. turkestanicus Knorring
L. balchanicus Czerniak., L. gypsaceus Vved.,
L. inebrians Bunge, L. cabulicus Benth.
L. acutilobus (Ledeb.) Fisch. et C. A. Mey.,
L. botschantzevii Kamelin et Zukerv.,
L. diacanthophyllus (Pall.) Benth., L. gypsaceus Vved.,
L. hirsutissimus Vved., L. inebrians Bunge,
L. knorringianus Pavlov, L. kschtutensis Knorr.,
L. nevskii Knorr., L. occultiflorus Rupr., L. olgae R.
Kamelin, L. paulsenii Briq., L. pubescens Vved.,
L. platyacanthus Rupr., L. setulosus Vved.,
L. platycalyx Schrenk, L. seravschanicus Knorr.,
L. vvedenskyi R. Kam. et Zucker.
Turkmenistan
Uzbekistan
Nuratau and Kyzylkum
deserts, Tian-Shan and
Pamir-Alay Mountains
https:
//wcsp.science.kew.org/
https:
//wcsp.science.kew.org/
[13,15]
5. Traditional Uses
The traditional use of Lagochilus plants dates back centuries. L. inebrians is commonly
known as Inebriating Mint, Intoxicating Mint, Turkistan Mint, or Intoxicating Hare’s Lip.
The name L. inebrians is derived from the Greek words “lagos” and “cheilos”, literally
meaning “hare” and “lip/cheek” and “inebrians”, meaning intoxicating, thus translating
to “intoxicating hare’s lip” (Wikipedia). A decoction of herb and roots of Lagochilus species
are used in folk medicine as a styptic and also against skin conditions, stomach pain, and as
tranquilizers. Many species of the Lagochilus genus have been used in traditional medicine
to treat hemorrhages and inflammation [8,9]. The most commonly reported effects include
relaxation, euphoria, and subtle perceptual changes. It is also used for the treatment of
allergies and skin diseases. In Central Asia, L. inebrians has been used during celebrations
for its intoxicating and sedative effects [22]. People make infusions with the dried leaves
of L. inebrians; honey and sugar are often added to this drink to reduce its bitter taste.
A summary of their traditional use is presented in Table 2.
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Table 2. Ethnomedicinal uses of different Lagochilus species and the used parts.
Species
Country
Parts Used
Traditional Uses
Reference
L. cabulicus
Iran
aerial parts
[23,24]
L. gypsaceus
Uzbekistan
aerial parts
L. hirtus
Xinjiang, China
whole plant
L. ilicifolius
Ningxia, China
whole plant
L. inebrians
Uzbekistan
L. lanatonodus
L. leiacanthus
L. platycalyx
L. platyacanthus
Xinjiang, China
Xinjiang, China
Uzbekistan
leaves, stems, fruits,
inflorescences
aerial parts
whole plant
leaves
Xinjiang, China
whole plant
for animals with lung trouble
hemostatic, sedative effect, decrease in blood pressure,
hemorrhage (traumatic, uterine, hemorrhoidal,
pulmonary, lung, and nasal), hemophilia
styptic, antihemorrhagic, coronary heart diseases,
angina pectoris, ulcer, insomnia, amnesia
hemostatic, inflammation, ulcer, hemostasis, spasm,
anti-edema, coronary heart disease, angina pectoris,
insomnia, dementia
antihemorrhagic, allergic dermatosis, skin illnesses,
stomach pain, tranquillizer, intoxicating effect, sedative
antihemorrhagic, against allergic dermatosis
hemostatic, inflammation, ulcer
sedative and hypotensive action
antihemorrhagic, coronary heart diseases, angina
pectoris, ulcer, insomnia, and amnesia
[9,25]
[10,26]
[5–7]
[5,8,9]
[6,7,27]
[28]
[29]
[10,26]
6. Phytochemical Studies
Phytochemical studies performed on different Lagochilus species have demonstrated
the occurrence of several classes of primary and secondary metabolites. A literature survey
revealed that the genus Lagochilus is a rich source of diterpenoids [30–33], flavonoids [29,34],
phenolic compounds, triterpenoids [34], iridoid glycosides, lignans, steroids, alkaloids,
polysaccharides [35], volatile, non-volatile and aromatic compounds, lipids, carbohydrates,
minerals, vitamins, and others. About 150 secondary metabolites have been reported
from all previous classes in the genus. Among these compounds, diterpenoids have been
considered as useful taxonomic markers and the major active components of Lagochilus
species. In the following section (Table 3), we will summarize the reported natural products
isolated from each species. Out of 44 species presented in the genus, only 19 species have
been phytochemically explored. Therefore, the genus still holds more than half of its species
unseen by researchers.
Table 3. Chemical profiling of the isolated compounds from each Lagochilus species.
Species
Compounds
References
L. aucheri
germacrene D (107), α-pinene (108), β-bourbonene (109)
tricetin 3’-methylether (39), quercetin (40), quercetin 3-O-α-L-rhamnopyranosyl (1→6)
β-D-glucopyranoside (41), quercetin 3-O-β-D-glucopyranoside (42), α-pinene (108),
β-springene (110), geranyllinalool (111), sitosteryl acetate (122), stigmasteryl acetate (124),
lupeol (126)
lagochilin (1), lagochirsine (16), 7- cinnamoyllamalbide (106),
5-hydroxy-7,4′ -dimethoxyflavone (48), daucosterol (125), β-sitosterol (121),
8-acetylharpagide (99)
lagochilin (1), lagohirzidin (19), di-O-acetyllagohirsin (18) [33], lagochirzin, mono- and
diacetyllagochirsins (16–18) [37,39], stachydrine (127), tannins (2.0–3.3%), coumarins
(0.3–2.5%), lipids (4.25–8.30%) [41], diterpenoid lactone
quercetin (40), rutin (43), myricetin (44), isoquercitrin (45), kaempferol-3-O-rutinoside
(46), kaempferol-3-O-β-D-(6”-O-p-coumaryl) glycoside (47), (+)-syringaresinol (138),
scopoletin (150), 8-O-acetylharpagide (99), harpagide (100), ajugoside (101), ajujol (102),
geniposidic acid (103), mussaenosidic acid (104) and 8-deoxyshanzhiside (105), phytol
(142), 12-hentriacontanol (143), octacosanol (144), citrusin C (94),
4-(1E)-hydroxy-1-prophenyl)-2-methoxyphenol (95), 4-acetoxycinnamic acid (96),
3-methyl-1,2,3,4-tetrahydroquinoline (128), 4-hydroxyisoquinoline (129), songoramine
(130), songorine (131), erythro-1-[(4-O-β-D-glucopyranosyl-3-methoxyl)phenyl]-2-[(5’-methoxyl)-pinoresinol]-propane-1,3-diol (132), tortoside C (133),
sisymbrifolin (134)
[18]
L. cabulicus
L. gypsaceus
L. hirsutissimus
L. ilicifolius
[24,36]
[37–40]
[41–43]
[5–7,21]
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Table 3. Cont.
Species
L. inebrians
L. kotschyanus
L. lanatonodus
L. leiacanthus
L. macranthus
L. occultiflorus
L. olgae
L. platyacanthus
L. platycalyx
L. proskorjacovii
L. pubescens
L. setulosus
L. usunachmaticus
L. zeravschanicus
Compounds
lagochilin (1), lagochilin and its mono-, di-, tetraacetates (1–15), vulgarol and its acetate
(37–38), 5-hydroxy-4’,7-dimethoxyflavone (48), β-sitosterol (121), nonacosane (139),
hentriacontane (140), tritriacontane (141), 8-O-acetylharpagide (99), harpagide (100),
stachydrine (127)
α-pinene (108), myrcene (115), β-caryophyllene (116)
acetovanillone (72), androsin (97), neolloydosin (98), erythrodiol (118), β-sitosterol (121),
dacosyl ester (145), scopoletin (150)
15-demethoxyscupolin I (35), scupolin I (36), 5,2’,6’-trihydroxy-7,8-dimethoxyflavanone
(49), 5,2’,6’-trihydroxy-6,7,8-trimethoxyflavanone (50),
5,2’,6’-trihydroxy-7,8-dimethoxyflavanone-2’-O-β-D-glucoside (51),
5,2’-dihydroxy-7,8,6’-trimethoxyflavanone (53),
5,2’-dihydroxy-6,7,8,6’-tetramethoxyflavanone (54), pinocembrin (55), oroxylin A (56),
chrysin (57), 5,6-dihydroxy-7,8-dimethoxyflavone (58), isoscutellarein-8-methyl ester (59),
apigenin (60), hispidulin (61), 5,2’-dihydroxy- 6,7,8-trimethoxyflavone (62),
skullcapflavone I (63), 5,8- dihydroxy-7,2’-dimethoxyflavone (64), 5,2’,6’-trihydroxy6,7,8-trimethoxyflavone (65), 5,7,2’-trihydroxy-8,6’-dimethoxyflavone (66),
5,6,2’-trihydroxy-7,8,6’-trimethoxyflavone (67), neobaicalein (68), rivularin (69), oleanolic
acid (118), ursolic acid (119), vanillin (70), p-hydroxyacetophenone (71), acetovanillone
(72), dihydroxyskullcapflavanone I (73), wogonin (74), liquiritin (75), viscidulin II
2’-O-glucoside (76), 5,2’,6’-trihydroxy-6,7,8- trimethoxyflavone 2’-O-glucoside (77)
caryophyllene oxide (112), humulene epoxide II (113), viridiflorol (114)
laballenic (146), octadeca -5,8-dienoic (147), eicos -11-enoic (148) and eicosa-9,11-dienoic
acids (149)
lagochirsine (16)
lagoditerpenes A-E (20–24), (13E)-labd-l3-ene-8α,15-diol (25), leojaponins B (26),
leoheteronin D (27), enantioagathic acid (28), isocupressic acid (29), 7β,13
S-dihydroxylabda-8 (17),14-dien-19-oic acid (30),
8α,13(R),14(S/R),15-tetrahydroxylabdane (31), 15-nor-14-oxolabda-8(17),12E-diene-18-oic
acid (32), 12β,19-dihydroxymanoyl oxide (33), ent-12α,19-dihydroxy-13-epi-manoyl oxide
(34) (Zhang et al. 2015), rutin (43), apigenin (60), apigenin-7,4’-dimethylether (78),
acacetin (79), luteolin-7,3’,4’-trimethyl ether (80), luteolin-7,4’-dimethyl ether (81),
diosmetin (82), chrysoeriol (83), quercetin-3-O-rutinoside-7-O-glucoside (84), horridin
(85), apigenin-6,8-di-C-β-D-glucopyranoside (86), isorhamnetin-3-O-rutinoside (87),
isorhamnetin-3-O-robinobioside (88), isorhamnetin-3-O-β-D-glucoside (89),
isorhamnetin-3-O-rutinoside-4’-O-glucoside (90), lavandulifolioside (91),
8-O-acetylharpagide (99), geniposidic acid (103),
1-(4-hydroxy-3-methoxy)-phenyl-2-[4-(1,2,3-trihydroxypropyl)-2-methoxy]-phenoxy1,3-propandiol (135), (+)-isolarisiresinol 3-α-O-β-D-glucopyranoside (136),
(-)-isolarisiresinol 3-α-O-β-D-glucopyranoside (137)
quercetin (40), rutin (43), myricetin (44), kaemferol (92), 8-O-acetylharpagide (99),
harpagide (100), stachydrine (127)
lagochilin (1), tetraacetyllagochilin (10), 5-hydroxy-4’,7-dimethoxyflavone (48),
5,7-dihydroxy-3,4’-dimethoxyflavone (93), β-sitosterol (121), nonacosane (139)
15-mono-O-acetyllagochilin (3), 16-mono-O-acetyllagochilin (4),
3,18-di-O-acetyllagochilin (5), 15,16-di-O-acetyllagochilin (6),
3,15,18-tri-O-acetyllagochilin (7), 3,16,18-tri-O-acetyllagochilin (8),
15,16,18-tri-O-acetyllagochilin (9), tetraacetyllagochilin (10),
3,18-O-isopropylidenelagochilin-15-acetate (12),
3,18-O-isopropylidenelagochilin-15,16-diacetate (14), lagochilin (1),
di-O-isopropylidenelagochilins (5–6), 3,18-O-isopropylidenelagochilin (11),
16-O-acetyl-3,18-O-isopropylidenelagochilin (13),
di-O-acetyl-3,18-O-isopropylidenelagochilin (15), lagochilin (1),
3,18-O-isopropylidenelagochilin (11), 5-hydroxy-4’,7-dimethoxyflavone (48), β-sitosterol
(121), nonacosane (139), stachydrine (127)
lagochilin (1), 8-O-acetylharpagide (99), harpagide (100), lagochirsine (16), stachydrine
(127), ascorbic acid (151), β-carotene (152)
carbohydrates, polysaccharides, pectin, hemicellulose
polysaccharides, pectins, hemicelluloses
References
[32,37,40,44–55]
[19]
[27]
[28]
[56]
[57]
[37]
[58]
[29,42,52,53,59]
[12,60,61]
[30,31,53,60,62]
[37,39,52–54,63]
[64,65]
[35,64]
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In the following part, we will classify the isolated compounds from the species based
on their chemical structures. The most relevant citation about the isolation and characterization of these secondary metabolites will be given and highlighted.
6.1. Diterpenes
Diterpenes are the most characteristic and important phytochemicals in Lagochilus,
the highest numbers of which were reported in L. inebrians [48], L. pubescens [60], and
L. platyacanthus [26] (Table 4, Figure S1). Lagochilin (1) is the main component of the total
extractive substances of many species of the genus. Lagochilin (1) identified in L. inebrians,
L. setulosus, L. gypsaceus [37], L. hirsutissimus [33], L. proskorjacovii [61], and L. pubescens [62].
L. inebrians gathered in Samarkand province contained 2.3% lagochilin, L. setulosus gathered
in Chimkent province 1.1%, and L. gypsaceus gathered in Kashkadar’ya province 2.1% [66].
Lagochirsine (16) is found free in the three plant species L. hirsutissimus, L. setulosus, and
L. gypsaceus. However, its content in these plants was 0.2–0.3% [39].
Table 4. The isolated diterpenes of Lagochilus species as described in the literature.
Identified Compounds
Lagochilin (1)
3-Mono-O-acetyllagochilin (2)
15-Mono-O-acetyllagochilin (3)
16-Mono-O-acetyllagochilin (4)
3,18-di-O-Acetyllagochilin (5)
15,16-di-O-Acetyllagochilin (6)
3,15,18-tri-O-Acetyllagochilin (7)
3,16,18-tri-O-Acetyllagochilin (8)
15,16,18-tri-O-Acetyllagochilin (9)
tetra-Acetyllagochilin (10)
3,18-O-Isopropylidene-lagochilin (11)
3,18-O-Isopropylidene-lagochilin-15-acetate (12)
16-O-Acetyl-3,18-O-isopropylidene-lagochilin (13)
3,18-O-Isopropylidene-lagochilin-15,16-diacetate (14)
di-O-Acetyl-3,18-O-isopropylidene-lagochilin (15)
Lagochirsine (16)
O-Acetyl-lagohirsin (17)
di-O-Acetyl-lagohirsin (18)
Lagohirzidin (19)
Lagoditerpenes A (20)
Lagoditerpenes B (21)
Lagoditerpenes C (22)
Lagoditerpenes D (23)
Lagoditerpenes E (24)
(13E)-Labd-l3-ene-8α,15-diol (25)
Leojaponins B (26)
Leoheteronin D (27)
Enantioagathic acid (28)
Isocupressic acid (29)
7β,13 S-Dihydroxylabda-8 (17),14-dien-19-oic acid (30)
8α,13(R),14(S/R),15-Tetrahydroxylabdane (31)
15-Nor-14-oxolabda-8(17),12E-diene-18-oic acid (32)
12β,19-Dihydroxymanoyl oxide (33)
ent-12α,19-Dihydroxy-13-epi-manoyl oxide (34)
15-Demethoxyscupolin I (35)
Scupolin I (36)
Vulgarol (37)
Vulgarol acetate (38)
Sources
L. gypsaceus, L. inebrians, L. setulosus,
L. pubescens, L. proskorjacovii,
L. hirsutissimus
L. inebrians
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens,
L. proskorjacovii
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. inebrians, L. pubescens
L. hirsutissimus, L. setulosus,
L. gypsaceus, L. olgae
L. hirsutissimus
L. hirsutissimus
L. hirsutissimus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. leiacanthus
L. leiacanthus
L. inebrians
L. inebrians
Reference
[12,30,32,37,38,41,44–
49,60,61,63]
[12,30,32,37,38,41,44–49,60–63]
[32,44–49,60]
[32,44–49,60]
[31,32,44–49,60,62]
[31,32,44–49,60,62]
[32,44–49,60]
[32,44–49,60]
[32,44–49,60]
[12,32,44–49,60,61]
[30–32,44–49,60,62]
[30–32,44–49,60,62]
[30–32,44–49,60,62]
[30–32,44–49,60,62]
[30–32,44–49,60,62]
[37,39]
[37,39]
[33,37,39]
[33]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[26]
[28]
[26]
[44,45,47]
[44,45,47]
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6.2. Flavonoids and Phenolic Glycosides
Lagochilus species are characterized by rich biological activities, such as antioxidant,
anti-allergic, and enzyme inhibitory activities due in part to the presence of a diversity of
flavonoids and phenolic compounds [21,27–29,40,50,58]. Flavonoids accumulate in different plant parts of the Lagochilus species. It is believed that most flavonoids in the Lagochilus
are derivatives of quercetin, luteolin, and kaempferol. To date, about 60 flavonoids have
been identified in Lagochilus. The structural formulas of major flavonoids and their glycosides isolated or identified from raw materials of Lagochilus species are shown in Table 5
and Figure S2.
Table 5. The isolated phenylpropanoids of Lagochilus species described in the literature.
Identified compounds
Sources
Reference
Tricetin 3’-methylether (39)
L. cabulicus
Quercetin (40)
L. cabulicus, L. ilicifolius, L. platycalyx
Quercetin 3-O-α-L-rhamnopyranosyl (1→6)-β-D-glucopyranoside (41)
Quercetin 3-O-β-D-glucopyranoside (42)
L. cabulicus
L. cabulicus
L. ilicifolius, L. platyacanthus,
L. platycalyx
L. ilicifolius, L. platycalyx
L. ilicifolius
L. ilicifolius
L. ilicifolius
L. gypsaceus L. inebrians L. proskorjacovii,
L. pubescens
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus, L. platyacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus, L. lanatonodus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. leiacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
[23,36]
[7,23,29,36,
59]
[23,36]
[23,36]
Rutin (43)
Myricetin (44)
Isoquercitrin (45)
Kaempferol-3-O-rutinoside (46)
Kaempferol-3-O-β-D-(6”-O-p-coumaryl) glycoside (47)
5-Hydroxy-4’,7-dimethoxyflavone (48)
5,2’,6’-Trihydroxy-7,8-dimethoxyflavanone (49)
5,2’,6’-Trihydroxy-6,7,8-trimethoxyflavanone (50)
5,2’,6’-Trihydroxy-7,8-dimethoxyflavanone-2’-O-β-D-glucoside (51)
5,2’,6’-Trihydroxy-6,7,8-trimethoxyflavanone-2’-O-β-D-glucoside (52)
5,2’-Dihydroxy-7,8,6’-trimethoxyflavanone (53)
5,2’-Dihydroxy-6,7,8,6’-tetramethoxyflavanone (54)
Pinocembrin (55)
Oroxylin A (56)
Chrysin (57)
5,6-Dihydroxy-7,8-dimethoxyflavone (58)
Isoscutellarein-8-methyl ester (59)
Apigenin (60)
Hispidulin (61)
5,2’-Dihydroxy-6,7,8-trimethoxyflavone (62)
Skullcapflavone I (63)
5,8- Dihydroxy-7,2’-dimethoxyflavone (64)
5,2’,6’-Trihydroxy- 6,7,8-trimethoxyflavone (65)
5,7,2’-Trihydroxy-8,6’-dimethoxyflavone (66)
5,6,2’-Trihydroxy-7,8,6’-trimethoxyflavone (67)
Neobaicalein (68)
Rivularin (69)
Vanillin (70)
p-Hydroxyacetophenone (71)
Acetovanillone (72)
Dihydroxyskullcapflavanone I (73)
Wogonin (74)
Liquiritin (75)
Viscidulin II 2’-O-glucoside (76)
5,2’,6’-Trihydroxy-6,7,8- trimethoxyflavone 2’-O-glucoside (77)
Apigenin-7,4’-dimethylether (78)
Acacetin (79)
Luteolin-7,3’,4’-trimethyl ether (80)
Luteolin-7,4’-dimethyl ether (81)
Diosmetin (82)
[7,29,58,59]
[7,29,59]
[7]
[7]
[7]
[12,30,50,51,
60,61]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28,58]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[28]
[27,28]
[28]
[28]
[28]
[28]
[28]
[58]
[58]
[58]
[58]
[58]
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Table 5. Cont.
Identified compounds
Sources
Reference
Chrysoeriol (83)
Quercetin-3-O-rutinoside-7-O-glucoside (84)
Horridin (85)
Apigenin-6,8-di-C-β-D-glucopyranoside (86)
Isorhamnetin-3-O-rutinoside (87)
Isorhamnetin-3-O-robinobioside (88)
Isorhamnetin-3-O-β-D-glucoside (89)
Isorhamnetin-3-O-rutinoside-4’-O-glucoside (90)
Lavandulifolioside (91)
Kaemferol (92)
5,7-Dihydroxy-3,4’-dimethoxyflavone (93)
Citrusin C (94)
4-(1E)-Hydroxy-1-prophenyl)-2-methoxyphenol (95)
4-Acetoxycinnamic acid (96)
Androsin (97)
Neolloydosin (98)
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platyacanthus
L. platycalyx
L. pubescens
L. ilicifolius
L. ilicifolius
L. ilicifolius
L. lanatonodus
L. lanatonodus
[58]
[58]
[58]
[58]
[58]
[58]
[58]
[58]
[58]
[29,59]
[12,30,60,61]
[5,21]
[5,21]
[5,21]
[27]
[27]
6.3. Iridoids and Their Glycosides
Iridoids are a type of monoterpenoids in the general form of cyclopentanopyran and
are found in a wide variety of plants as glucosides. 8-O-Acetylharpagide (99) and harpagide
(100) are common iridoids in Lagochilus [6,50,52]. The latest results of our investigations
showed that L. inebrians and L. gypcaseus are rich for 8-O-acetylharpagide [40,50]. However,
only a few (seven) iridoids could be reported in the genus. From the aerial parts of
L. ilicifolius ajugoside (101), ajugol (102), geniposidic acid (103), mussaenosidic acid (104),
and 8-deoxyshanzhiside (105) were identified and isolated [5,58] (Table 3, Figure S3).
6.4. Essential Oils
The species of Lagochilus are aromatic with a pleasant scent. Germacrene D (107), αpinene (108), and β-bourbonene (109) are the main components of the oil of L. aucheri [18].
In the oil of L. cabulicus α-pinene (108), β-springene (110), and geranyllinalool (111) are
major compounds [23]. The oil of L. macranthus mainly contains the oxygenated sesquiterpenes caryophyllene oxide (112), humulene epoxide II (113), and viridiflorol (114) [56]. The
major constituents of L. kotschyanus appear to be α-pinene (108), myrcene (115), and βcaryophyllene (116), respectively [19]. In the oil of L. diacanthophyllus, the main components
are α-pinene (108) and dillapiol (117) [67,68]. The chemical composition of three Lagochilus
species essential oils: L. gypsaceus, L. inebrians, and L. setulosus, were determined using
the GC-MS method [69]. The results showed that the studied essential oils are made up
mainly of linalool, β-ionone, trans-chrysanthenyl acetate, α-terpineol for L. gypsaceus; transchrysanthenyl acetate, eugenol, trans-verbenol, bicyclo [3.1.1]hept-3-en-2-one, pinocarvone
for L. inebrians; and finally 2,4-bis(1,1-dimethylethyl)phenol, bicyclo[3.1.1]hept-2-en-4-ol,
hexadecanoic acid, limonene, 2-hexenal for L. setulosus. Our results indicated that limonene,
furfural, benzaldehyde, 4-terpineol, myrtenal, α-terpineol, myrtenol, and p-cymen-7-ol
are the common compounds to these species. Monoterpens linalool, trans-chrysanthenyl
acetate, α-terpineol, eugenol have been reported as the most abundant compounds in
the oil of L. gypsaceus and L. inebrians, while L. setulosus oil consists of aliphatic alcohol,
aldehyde, and ketons. Especially, oxygenated monoterpenes trans-chrysanthenyl acetate
and eugenol were found for the first time in substantial amounts in the oil from L. gypsaceus and L. inebrians. A comparison of our studies confirms that the dissimilarities in
the composition of the essential oils of three Lagochilus species may be considered as an
indication of several chemotypes existing within the genus (Table 3, Figure S4).
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6.5. Triterpenes
Plant triterpenoids represent a large and structurally diverse class of natural products.
However, they represent a minor class of compounds reported from Lagochilus species.
Only erythrodiol (118) from L. lanatonodus [27], oleanolic (119), and ursolic acid (120) from
L. leiacanthus [28] were isolated (Table 3, Figure S5).
6.6. Steroids
Plant steroids are a diverse group of secondary metabolites. Up to now, phytochemical
studies have afforded six steroids from the Lagochilus genus, which sitosteryl acetate (122),
stigmasteryl acetate (124), lupeol (126) from L. cabulicus [23,36] (Table 3, Figure S6). L. gypsaceus afforded daucosterol (125) and β-sitosterol (121) [40]. β-Sitosterol (121), stigmasterol
(123), and daucosterol (125) were isolated from L. inebrians [50]. β-Sitosterol (121) was
identified in L. lanatonodus and L. pubescens [12,27,30,51,60,61].
6.7. Alkaloids
Alkaloids are a group of important secondary metabolites. Alkaloids and extracts
of alkaloid-containing plants have been used throughout human history as remedies,
poisons, and psychoactive drugs. Stachydrine has been identified in many Lamiaceae
species [53,54]. Multiple studies have confirmed that stachydrine has strong neuroprotective, anti-fibrotic, and anti-inflammatory effects [70]. Stachydrine (127) was reported
in L. inebrians and L. hirsutissimus [42,54,63]. 3-Methyl-1,2,3,4-tetrahydroquinoline (128),
4-hydroxyisoquinoline (129), songoramine (130), and songorine (131) were determined
from L. ilicifolius [21] (Table 3, Figure S7).
6.8. Lignans
The lignans are fiber-associated compounds found in plants, particularly seeds, nuts,
grains, and vegetables. Lignans are rare in the Lagochilus genus, with only three lignans named erythro-1-[(4-O-β-D-glucopyranosyl-3-methoxyl)- phenyl]-2-[(5’-methoxyl)pinoresinol]-propane-1,3-diol (132), tortoside C (133), and sisymbrifolin (134) isolated
from L. ilicifolius [7] (Table 3, Figure S8). Another three lignans: 1-(4-hydroxy-3-methoxy)phenyl-2-[4-(1, 2, 3-trihydroxypropyl)-2-methoxy]-phenoxy- 1, 3-propandiol (135), (+)isolarisiresinol 3-α-O-β-D-glucopyranoside (136), and (-)-isolarisiresinol 3-α-O-β-Dglucopyranoside (137) were isolated from whole herb of L. platyacanthus [58]. From L. ilicifolius (+)-syringaresinol (138) was identified by Qian et al. [7].
6.9. Aliphatic Alkanes and Alcohols
Plants have an outer surface layer of wax, which is usually a complex mixture of
aliphatic lipid compounds, such as straight and branched chain alkanes, alkenes, long-chain
fatty acids and esters, long-chain fatty alcohols, long-chain fatty aldehydes, and ketones.
Nonacosane (139) (in L. inebrians, L. proskorjacovii, L. pubescens) [12,51,60,61], hentriacontane
(140), tritriacontane (141) (in L. inebrians) [51], phytol (142), 12-hentriacontanol (143), and
octacosanol (144) (in L. ilicifolius) [5], dacosyl ester (145) (in L. lanatonodus) [27] are present
in Lagochilus species (Table 3, Figure S9).
6.10. Lipids
In plants, lipids play especially important roles as signaling and energy storage
compounds [55]. Lipid compounds were identified and analyzed in Lagochilus species
by some researchers [41,55,57]. Laballenic (146), octadeca -5,8-dienoic (147), eicos -11enoic (148), and eicosa-9,11-dienoic acids (149) were detected in L. occultifloris [57] (Table 3,
Figure S10). Free and polar lipids from ripe seeds of L. inebrians were investigated by
Yuldasheva et al. [55], and the findings showed that seeds have a very high percentage of
oil content, a large fraction of unsaturated ω-3 and ω-6 fatty acids.
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6.11. Miscellaneous Compounds
Some other metabolites were also discovered in this genus, such as scopoletin (150) [7,27,41],
ascorbic acid (151), β-caroten (152) [63] (Figure S11). The following class of metabolites
were identified in Lagochilus species: carbohydrates [35,64], sugars [63], polysaccharides,
pectin, hemicellulose [64,65,71], tannins [63], organic acids, resins [63], and microelements [63,72,73].
7. Biological Activities
The biological activities, including hemostatic, antibacterial, anti-inflammatory, antiallergic, cytotoxic, enzyme inhibitory, antispasmodic, sedative, hypotensive, psychoactive,
and other activities, have been reported in some publications. Different biological activities have been reported from the extracts, fractions, essential oils, and their isolated
compounds. Mostly, Lagochilus species have been used as a folk medicine for treating
hemostatic [10,11,25,35,39,58,64,65,71,74–85], inflammation [10,85–87], and ulcers [7] in
Chinese and Central Asian traditional medicine. Reported biological activities of the
genus Lagochilus are written in subcategories below.
7.1. Hemostatic Effect
The plants of the genus Lagochilus have been known for their therapeutic effects and have been
included in medicinal practice as valuable hemostatic agents [10,11,25,35,39,58,64,65,71,74–85].
The mechanism of the hemostatic action of Lagochilus preparations was evaluated using
different in vivo tests (Table 6). The extracts of Lagochilus species have shown a promising
activity when applied to treat hemophilia. In China and Central Asian countries, the
species of Lagochilus are widely used as effective hemostatic agents.
Table 6. The hemostatic effect of different Lagochilus species extracts and their isolated components.
Species
Tested Sample
Test Type
Lagochilus species
Lagochilus preparations
in vivo
Lagochilus species
lagochiline acetic
acid ester
in vivo
Lagochilus species
Lagochilus infusion and
pure lagochilin (1)
in vivo
L. inebrians
Lagoden drug (5%
solution of lagohirisine
sodium salt) has been
developed and
approved for public use
in vivo
Main Finding
increased the coagulation ability of the blood
both by activating plasma and cellular blood
coagulation factors and by depressing the
anticoagulant system, and also have a
suppressive effect on plasma fibrinolytic activity;
accelerating the blood coagulation process,
reducing vascular permeability, lowering blood
pressure, sedative and analgesic effects
showed sedative properties; LD50 for mice was
3.6 g/kg. Injected subcutaneously into rabbits in
doses of 0.05 g/kg, it hastened the process of
blood coagulation by 30–40%; it affected a
reduction in the bleeding time and the volume of
blood lost
in doses of 0.05 g/kg in dogs shortened the
blood-clotting and prothrombin times by 40–60%;
the effects were even more pronounced in
dicoumarol hemophilia.
Lagoden is prescribed for the treatment and
prevention of acute and chronic bleeding
(gastrointestinal, hemorrhoidal, pulmonary,
uterine, etc.), parenchymal hemorrhage (renal,
splenic, brain), capillary, and other bleeding, for
surgical interventions in otolaryngology practice
(for tonsillary tumors, juvenile nasopharyngeal
angiofibroma), microsurgery on the ear, etc., in
dentistry for removing teeth, cysts, granulomas,
during surgery of the gastrointestinal tract,
prostate adenomectomy, gynecological operations
on the uterus, including bleeding associated with
a violation of the blood coagulation system
Reference
[25,74–77]
[78]
[79]
Pharmacological
Committee of
the Republic of
Uzbekistan
(registration
Certificate N
01/195/1 of
08.05.2001)
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Table 6. Cont.
Species
Tested Sample
Test Type
Main Finding
Reference
L. inebrians
Inebrin drug
(extractive substances)
in vivo
recommended in the form of tablets for the
treatment of chronic uterine, nasal,
gastrointestinal, and other bleeding
[80–82]
in vivo
hemostatic activity
[11,39,71,82,83]
in vivo
possessed a marked direct-action activity and
exceeded heparin during affection
[35,64,65]
L. inebrians
L. usunachmaticus
compound 1 and 16
and their natural and
synthetic derivatives
(with cellulose acetate,
mono-, di-, tri- and
tetrasodium succinates,
supramolecular
complexes of lagochilin
with glycyrrhizic acid
and its
monoammonium
salt, etc.)
polysaccharides and
carbohydrates isolated
from the epigeal part of
the plant
L. setulosus
Setulin (obtained from
a dry extract of
the plant)
in vivo
L. diacanthophyllus
H2 O and 95%
EtOH extracts
in vivo
L. platyacanthus
lagoditerpenes 20, 21
and 24
in vivo
L. lanatonodus, L.
diacanthophyllus, L.
platyacanthus L.
hirtus, L. ilicifolius
H2 O and EtOH extracts
in vivo
Setulin hemostatic drug excipient in rabbits in a
dose of 50 mg/kg causes the expressed
hemostatic effect associated with the activation of
thromboplastin formation and transformation of
prothrombin into thrombin owing to the
acceleration of contact and phospholipid
coagulation starting mechanisms (I and II phases
of blood coagulation). At 60–90 min after
introduction, Setulin completely removes the
hypocoagulative effect of heparin
EtOH extract significantly shorten the clotting
time of mice, bleeding time, show some
hemostatic activity
lagoditerpenes 20, 21, and 24 showed that
moderate hemostatic activities by shortening the
values of activated partial thromboplastin time
(APTT). These compounds were able to shorten
the values of APTT, while the values of
prothrombin time and thromboplastin time were
not obviously shorted
L. lanatonodus and L. diacanthophyllus showed
better hemostatic activities among five species.
The extracts of L. lanatonodus and
L. diacanthophyllus showed dose-dependent
hemostatic effects. Both H2 O and EtOH extracts
of L. lanatonodus at 400 mg/kg in rats greatly
reduced the blood clotting time and tail
bleeding time
[84]
[85]
[58]
[10]
7.2. Anti-Inflammatory Activity
Some species of the Lagochilus genus have been used in Chinese traditional medicine
to treat inflammation. The results of anti-inflammatory activities of the components from
Lagochilus species are summarized in Table 7 [10,85–87]. This could be due to iridoid
glucosides, which have been shown to be potent anti-inflammatory compounds [10,85].
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Table 7. The anti-inflammatory activities of different Lagochilus species extracts.
Species
Tested Sample
Test Performed
L. inebrians
5% infusion of leaves
in vivo
L. inebrians
tincture of aerial parts
in vivo
L. diacanthophyllus
H2 O extract or 95%
EtOH extract
in vivo
L. diacanthophyllus
H2 O extract or 95%
EtOH extract
in vitro
five Lagochilus species
(L. hirtus, L. platyacanthus,
L. lanatonodus,
L. diacanthophyllus, and
L. ilicifolius)
H2 O and EtOH extracts
in vivo
Main Finding
from 10 guinea pigs, 8 were less
sensitive to L. inebrians
most active inhibitor of edema in frog
legs among the tested samples
extracts can suppress xylene-induced
ear edema in mice, showed some
anti-inflammatory activity in vivo
EtOH extract significantly inhibit
macrophage release of NO, TNF-α, IL-6,
showed strong in vitro
anti-inflammatory activity
the extracts of L. lanatonodus and
L. diacanthophyllus showed strong
inhibitory effects on the acute phase of
inflammation in both xylene-induced
ear edema mouse model and
carrageenan-induced paw edema rat
model. Aqueous extract of L. lanatonodus
showed the best anti-inflammatory
activities among the five Lagochilus
species. L. lanatonodus extracts can
significantly modulate inflammatory
indexes, that is, lower NO, MDA, and
PEG2 and elevate SOD. L. platyacanthus,
L. hirtus, and L. ilicifolius, exhibited little
potency in alleviating edema
Reference
[86]
[87]
[85]
[85]
[10]
7.3. Antibacterial Activity
The antibacterial effect of the components (different extracts, essential oils, total alkaloids,
and some individual compounds) from Lagochilus species were evaluated [5–7,19,21,24,88].
The results indicated that the components of L. ilicifolius, L. cabulicus, L. acutilobus, L. gypsaceus, L. inebrians, L. olgae, L. proskorjakovii, L. setulosus, L. vvedenskyi had weak antibacterial
effects on human pathogens (Table 8). However, Taban et al. [19] reported that the essential
oil obtained from the flowers of L. kotschyanus showed strong inhibitory activity against
Gram-positive bacteria S. pyogenes, S. agalactia, and B. anthracis (MIC 3.1 mg/mL).
Table 8. The antibacterial activities of the components from Lagochilus species.
Species
Tested sample
L. ilicifolius
EtOH, petroleum ether,
CHCl3 , EtOAc,
n-BuOH extracts, water
remainder, and
total alkaloids
S. aureus, B. subtilis,
B. cereus, E. coli
L. kotschyanus
essential oils of flowers
and leaves
S. aureus, S. pyogenes,
S. agalactia, B. anthracis,
K. pneumoniae,
P. aeruginosa
H2 O and EtOH extracts
S. aureus ATCC 6538;
E. coli ATCC 11229;
B. subtilis ATCC 6633;
P. aeriginosa ATCC 9027
L. cabulicus
Microorganism
Main finding
EtOAc ext. inhibited B. subtilis
(3.0 ± 0.1 mm), EtOH, EtOAc,
n-BuOH extracts inhibited B. cereus
(5.0 ± 0.1 mm) (at 100 µg/disc
concentration)
flowers oil showed strong inhibitory
activity against S. pyogenes, S. agalactia,
B. anthracis, K. pneumoniae, and
P. aeruginosa; leaves oil only showed
inhibitory activity against S. pyogenes
only EtOH extract inhibited S. aureus
ATCC 6538 at 0.5 mg/mL
Reference
[5–7,21]
[19]
[24]
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Table 8. Cont.
Species
Tested sample
L. acutilobus,
L. gypsaceus,
L. inebrians, L. olgae,
L. proskorjakovii,
L. setulosus,
L. vvedenskyi
compounds lagochilin
(1), 5-hydroxy-4’,7dimethoxyflavone (48),
8-O-acetylharpagide
(99), β-sitosterol (121),
stigmasterol (123),
daucosterol (125),
MeOH extracts
obtained from the
aerial parts of plants
Microorganism
Main finding
Reference
S. aureus ATCC 25923,
B. subtilis RKMUz 5,
P. aeruginosa ATCC
27879, E. coli RKMUz
221, C. albicans
RKMUz 247
compounds 1, 48, 99, 121, 123, 125
were inactive against the tested
microorganisms; B. subtilis
(9.12 ± 0.13 mm for MeOH ext. of
L. proskorjakovii and 9.04 ± 0.10 mm
for MeOH ext. of L. olgae) MeOH
extracts of L. inebrians, L. olgae, and
L. proskorjakovii were more active
against B. subtilis with
MIC = 125 µg/mL
[88]
7.4. Antioxidant Activity
The antioxidant activity of methanol extracts of seven Lagochihis species was evaluated
using a metal chelating (MC), phosphomolybdenum (PPBD), ferric reducing power (FRAP),
cupric reducing antioxidant capacity (CUPRAC), 2,2’-azino-bis (3-ethylbenzothiazoline-6sulphonic acid) (ABTS), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. In these assays,
we reported the antioxidant activities as Trolox equivalents, whereas ethylenediaminetetraacetic acid (EDTA) was used for metal chelating assay [40]. Regarding quenching of
DPPH radical activity, the observed abilities decreased in the order: L. inebrans (collected
from Djizzakh)>L. vvedenskyi>L. olgae>L. setulosus>L. proskorjakovii>L. gypsaceus>L. acutilobus>L. inebrans (collected from the Surkhandarya region). Similar to DPPH, the best
cupric (CUPRAC) and ferric reducing power (FRAP) ability were determined by L. inebrans
(from Djjzzakh), followed by L. vvedenskyi. The antioxidant activity is probably due to
the polyphenols present. The highest amount of total phenolic compounds was found
in L. inebrans, followed by L. vvedenskyi and L. proskorjakovii, and we observed a strong
correlation between total phenolic content and antioxidant (DPPH, CUPRAC, and FRAP)
properties of the tested extracts. In the PPBD assay, L. proskorjakovii exhibited the strongest
ability with 2.00 mmolTE/g, while L. inebrians (from Surkhandarya) was the weakest.
In the ferrozine assay, the MC ability of L. acutilobus was the best, followed by L. olgae
and L. setulosus. We also evaluated the antioxidant potential of 3 Lagochilus essential oils
mentioned above in vitro assays [69]. L. inebrians oil exhibited the best antioxidant effect
in these assays. For example, L. inebrians had about a 16-fold higher activity than that of
L. setulosus in DPPH assay. Similarly, L. inebrians exhibited a significant reducing power
effect with 2093.33 mgTE/g in FRAP assay. The second highest antioxidant value was
noted in L. setulosus, except for the MC assay. The observed activity for L. inebrians may be
explained with its chemical profiles. The main components (trans-chrysanthenyl acetate,
eugenol, and verbenol) have already been reported as strong antioxidant compounds, and
they could be considered as the main contributors to the observed activity [69]. On the
other hand, only very rare work could be traced regarding the in vivo antioxidant activity
of the plants belonging to the genus Lagochilus. Only three species were examined by Jiao
et al. [10] for their effect on inducible nitric oxide synthase, malondialdehyde, and superoxide dismutase. In this study, both aqueous and alcohol extracts of L. lanatonodus were able
to inhibit the enzymes at 200 and 400 mg/kg doses similar to aspirin (positive control).
7.5. Anti-Allergic Activity
Lagochilus leiacanthus is a folk medicine used for the treatment of inflammation and
ulcers in Xinjiang, China. Mast cells and basophils play a central role in allergic and
inflammatory reactions. The β-hexosaminidase release from RBL-2H3 (rat basophilic
leukemia) mast cells was measured as an indicator of the inhibitory activity against allergic
reactions. In biological studies on the alcoholic extracts of the whole herb of this plant,
Furukawa et al. [28] found that the extract inhibits the release of β-hexosaminidase from
RBL-2H3 cells. They also examined the inhibitory activity of the isolated compounds.
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Among the isolated compounds, flavanones 51–52 and flavones 54, 56, 61, 65–67 showed
inhibition of β-hexosaminidase release more potently than ketotifen used as a positive
control. It is worth mentioning that no work could be found regarding the in vivo antiallergic effect of Lagochilus species, although most of these plants showed promising
anti-inflammatory activity. This point might present a future point for many researchers.
7.6. Cytotoxic Activity
The whole herb of L. ilicifolius has been used as a folk medicine for treating hemostatic,
inflammation, and ulcers in China. The cytotoxic activities of three lignans 132–134 isolated
from L. ilicifolius were evaluated using the MTT assay against the PC12 cell line derived
from rat adrenal pheochromocytoma [7]. Erythro-1-[(4-O-β-D-glucopyranosyl-3-methoxyl)phenyl]-2-[(5’-methoxyl)-pinoresinol]-propane -1,3-diol (132) exhibited strong cytotoxic
activity against PC12 cell line with an IC50 value of 1.22 ± 0.03 µmol/L, while sisymbrifolin
and tortoside C was not cytotoxic.
7.7. Enzyme Inhibition
Urease plays an important role in the pathogenesis of many illnesses, such as pyelonephritis, hepatic coma, and peptic ulceration. Tyrosinase plays an important role in melanogenesis (i.e., biosynthesis of melanin pigments, also known as pigmentation). Amylase
is an enzyme produced primarily by the pancreas and the salivary glands to help digest
carbohydrates. Acetylcholinesterase (AChE) is one of the most efficient enzymes of the
nervous system. AChE inhibitors are employed in the treatment of Alzheimer’s disease,
myasthenia gravis, glaucoma, smooth muscle atony, and assorted disorders of autonomic
nervous system functions. The results of inhibitory enzyme activities of the components
from Lagochilus species are summarized in Table 9 [34,40,69].
Table 9. Enzyme inhibitory activities of the components from Lagochilus species.
Species
Tested Sample
Enzyme
L. cabulicus
EtOAc and MeOH ext
urease
L. inebrians, L. setulosus,
L. gypsaceus
essential oils
AChE, BChE,
tyrosinase, glucosidase,
amylase
L. acutilobus,
L. gypsaceus, L. inebrians,
L. olgae, L. proskorjakovii,
L. setulosus,
L. vvedenskyi
MeOH extracts and
compounds lagochilin
(1), 5-hydroxy-4’,7dimethoxyflavone (48),
8-O-acetylharpagide
(99), β-sitosterol (121),
daucosterol (125)
AChE, BChE,
tyrosinase, glucosidase,
amylase
Main Finding
the extracts showed no Jack
bean urease inhibitory activity
no inhibition was observed by
L. gypsaceus EO; L. setulosus EO
had no effect against
glucosidase; tyrosinase
inhibitory activity of EO
followed L. inebrans>L. setulosus>L. gypsaceus; L. setulosus
EO and L. inebrans EO showed
amylase and glucosidase
inhibitory effects
compound 48 exhibited the
strongest inhibitory effects on
both AChE and BChE; the
highest tyrosinase inhibitory
effect was found for MeOH ext
of L. inebrians (from Djizzakh)
and 48; MeOH ext of
L. acutilobus and 48 showed the
best amylase inhibitory effects;
MeOH ext of L. inebrians and
48 exhibited stronger
glucosidase inhibitory effects;
compound 99 had the weakest
effect on tested enzymes
Reference
[34]
[69]
[40,88]
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7.8. Acute Toxicity
Oral administration of Lagochilus extracts, including aqueous and ethanol extracts
from L. lanatonodus, L. diacanthophyllus, L. platyacanthus, L. hirtus, and L. ilicifolius, did not
show visible signs of toxicity in mice at the highest dose of 5000 mg/kg of body weight [10].
An acute toxicity study was performed in mice according to the Organization for Economic
Cooperation and Development (OECD/OCED) guidelines 423 (Acute Oral Toxicity-Acute
Toxicity Class Method) [89] with each group comprising of ten mice. The animals were
orally administered a dose of 5000 mg/kg aqueous and ethanol extracts from five Lagochilus
species and were observed continuously for 30 min and 4 h, intermittently for 24 h, and
then once a day for the next 14 days for general behavioral change, signs of toxicity and
mortality. There was no evidence of differences in physiological or behavioral responses
between the normal control group and extract-treated groups and also no differences in the
consumption of food and water, which implied that the five Lagochilus species are not toxic.
7.9. Other Activities
Preliminary biological investigations on Lagochilus components (extracts, fractions,
and individual compounds) have indicated their antispasmodic [90], sedative and hypotensive [29], psychoactive [91], and other activities. Lagochilus components may be
valuable in the treatment of glaucoma [92], dermoplasty [93], hypertension, heart failure,
and angina [29,94].
Lagochilus species have been traditionally and ethnopharmacologically used to treat
many diseases, such as hemorrhages, inflammation, allergies, skin diseases, and stomach
pain. The phytochemical and biological results validate and support the ethnopharmacological use of Lagochilus species in traditional medicine. Various chemical constituents have
been isolated and identified in different groups of compounds, e.g., flavonoids, diterpenes,
terpenoids, steroids, iridoids, polysaccharides, and other compounds. Diterpenes and
flavonoids are the main bioactive compounds in Lagochilus species, and a wide spectrum
of biological studies have focused on these compounds. However, the biological effects
of other compounds, such as terpenoids, steroids, iridoids, polysaccharides isolated from
this genus, have mostly not been investigated. In certain cases, only plant extracts have
been tested for biological activities. Lagochilus species are a valuable medicinal resource
with specific pharmacological activities in vitro and in vivo studies; however, more comprehensive studies on their pharmacokinetics, metabolism, side effects, and toxicity are
required to demonstrate the efficacy and safety of plant extracts or bioactive compounds
from this genus.
8. Conclusions
We conclude that the genus Lagochilus is a good source of phytochemical diversity.
This genus is native to Central, South-Central, and Eastern Asia and is mainly distributed
in arid and semiarid regions of China, Kazakhstan, Uzbekistan, Mongolia, Iran, Pakistan,
Afghanistan, and endemic to the Asian mountains. The obtained results demonstrated
that not even the well-studied species of Lagochilus had been exhaustively investigated
for secondary metabolites, and it should certainly be worthwhile to explore them for new
bioactive molecules further. Some species of Lagochilus are rare in nature and endangered.
Due to the rapid economic development of regions, climate change, over-collection by
people, and continuing resource exploitation, some species in this genus face severe threats,
and serious efforts are needed to save and protect rare and endangered species from
overharvesting and extinction. Efforts should, therefore, be made to cultivate and naturalize
the economically relevant species.
Supplementary Materials: The following are available online at https://www.mdpi.com/2223-7
747/10/1/132/s1, The chemical structures isolated from Lagochilus species are available online,
alongside Figures S1–S11. Figure S1. Chemical structures of isolated diterpenes from the genus
Lagochilus, Figure S2. Chemical structures of isolated phenylpraponoids from the genus Lagochilus,
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Figure S3. Chemical structures of isolated iridoids from the genus Lagochilus, Figure S4. Chemical
structures of some isolated terpenoids from the genus Lagochilus, Figure S5. Chemical structures of
isolated triterpenoids from the genus Lagochilus, Figure S6. Chemical structures of isolated steroids
from the genus Lagochilus, Figure S7. Chemical structures of isolated alkaloids from the genus
Lagochilus, Figure S8. Chemical structures of isolated lignans from the genus Lagochilus, Figure S9.
Chemical structures of isolated aliphatic alkanes and alcohols from the genus Lagochilus, Figure S10.
Chemical structures of some of isolated lipids from the genus Lagochilus, Figure S11. Chemical
structures of other isolated compounds from the genus Lagochilus.
Author Contributions: N.Z.M. and D.K.A. conceptualization and writing the original draft preparation; C.L., H.H. and K.S.T. collecting of data; E.A. and M.L.A. revising and funding; L.A.W. and M.W.
review and editing. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Deanship of Scientific Research at Princess Nourah bint
Abdulrahman University through the Fast-track Research Funding Program.
Acknowledgments: The authors (N.Z.M. and H.H.) thank the Alexander von Humboldt Foundation
for its generous support in providing the opportunity to do work in Germany. The authors extend
their appreciation to the Deanship of Scientific Research at Princess Nourah Bint Abdulrahman
University for funding this work through the Fast-track Research Funding Program.
Conflicts of Interest: The authors declare no conflict of interest.
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