New Compounds and Potential Candidates for Drug Discovery from Medicinal Plants of Vietnam

Abstract

The study of natural products introduces interesting new bioorganic structures and potential candidates for the drug discovery stage in the development of innovative drugs. Vietnam enjoys a broad biodiversity of native plant species, microorganisms, marine organisms, and a long tradition of using herbal remedies. Thus, the study of medicinal plants in determining the basis of their efficacy and safety is an important task for modern researchers in Vietnam. The present review covers literature on new compounds elucidated from the systematic study of medicinal plants within some popular genera in Vietnam, as well as their significant biological activities.

1. Introduction

Plants and their secondary metabolites have provided important drugs for modern medicine such as atropine, codeine, digoxin, morphine, quinine, and vincristine. Natural products are also significant as drug precursors, drug prototypes, and pharmacological probes.¹⁾ Modern drug discovery and development process can be divided into two major stages: drug discovery and drug development.²⁾ The drug discovery stage includes target discovery, lead discovery, and lead optimization. In the lead discovery phase a series of candidate compounds has been identified; the candidate compounds undergo lead optimization to identify a single active compound, after which the identified compound progresses into the drug development stage. The second major stage, drug development, begins with a single compound, which then progresses through various studies designed to support its approval as a new drug. The efficiency and selectivity of natural products toward particular molecular targets are related to the complexity and specificity of their three-dimensional structures; in regard to chemical diversity, natural products have no parallel among “pure” synthetic compounds.³⁾ The utility of natural products in drug discovery has been proven to be an outstanding source for innovative drugs.

Terrestrial and marine natural products are some of the most successful sources of drug leads for the treatment of many diseases and illnesses.⁴⁾ The diversity of living organisms is believed to be the cornerstone of success stories of natural biologically active compounds. In terms of opportunities for the identification of biologically active substances in relation to a broad biodiversity of species, and the long practice of using herbs to treat numerous diseases, Vietnam is privileged. The flora of Vietnam comprises more than 12000 plant species, about 1/3 of which (3948 species) have been used as medicinal plants in Vietnamese traditional medicine.^5–8) The number of known plant genera in Vietnam is 2256, belonging to 305 families. Vietnam’s bioflora features 57% of the global total number of plant families, 15% of plant genera, and 4% of plant species.⁹⁾

Medicinal plants are important in drug discovery as they often contain a vast number of biologically active natural products. Clinical trials have been conducted on medicinal plants over many years, and there has often been a correlation between the traditional uses of medicinal plants and the biological activities of their chemical constituents. Vietnam has a vast treasure of traditional medicinal plants. The study of the constituents of these plants, with a focus on medicinal plants used in Vietnam’s traditional medicine, is an important task for researchers in Vietnam. First, researchers have begun to explore the chemical profiles and biological and pharmacological properties of active constituents of traditional Vietnamese botanical medicines as the basis to understand and prove the purported medical efficacy of many traditional plants in treating a range of diseases and conditions. In addition, during this process, studies have shown many new and/or biologically active compounds which may be valuable to the drug discovery phase of creating innovative drugs. Due to the occurrence of a large number of scattered publications in recent years, this review outlines the most successful research on new compounds from systematic studies of medicinal plants within some popular genera used as herbal medicines in Vietnam, as well as the significance of their biological activities. In particular, this review covers studies on new natural products from six plant genera in Vietnam: Croton, Mallotus, Artemisia, Goniothalamus, Garcinia, and Ficus.

2. New Compounds from Plants of Vietnam

2.1. The Genus Croton

Croton is a large genus of the Euphorbiaceae family, comprising around 1300 species of trees, shrubs, and herbs distributed in the tropical and subtropical regions of both hemispheres.¹⁰⁾ More than forty Croton species are listed in Vietnam: C. alpinus A. CHEV. ex GAGNEP., C. argyratus BLUME, C. bonianus GAGNEP., C. budopensis GAGNEP., C. caryocarpus CROIZ., C. cascarilloides RAEUSCH., C. caudatus GEISELER, C. chevalieri GAGNEP., C. crassifolius GEISEL, C. cubiensis GAGNEP., C. dalatensis THIN, C. delpyi GAGNEP., C. dodecamerus GAGNEP., C. dongnaiensis PIERRE ex GAGNEP., C. eberhardtii GAGNEP., C. glandulosus L., C. heterocarpus MUELL.-ARG., C. ignifex CROIZ., C. joufra ROXB., C. kongensis GAGNEP., C. krabas GAGNEP., C. lachnocarpus BENTH., C. laevigatus VAHL, C. lamdongensis THIN, C. langsonensis THIN, C. laoticus GAGNEP., C. lasianthus PERS., C. latsonensis GAGNEP., C. limitincola CROIZ., C. longipes GAGNEP., C. maieuticus GAGNEP., C. murex CROIZ., C. phuquocensis CROIZ., C. pontis CROIZ., C. poilanei GAGNEP., C. potabilis CROIZ., C. roxburghii BALAKR., C. salicifolius GAGNEP., C. scopuligenus CROIZ., C. thoii THIN, C. thorelii GAGNEP., C. tiglium L., C. tonkinensis GAGNEP., C. touranensis GAGNEP., and C. yunannensis W. W. SMITH.⁹⁾

C. tonkinensis GAGNEP. (Euphorbiaceae) is a small plant, native in Northern Vietnam, and grows to 1–1.5 m in height. In Vietnamese traditional medicine, the leaves of C. tonkinensis are prescribed as a remedy for stomach ache, gastric and duodenal ulcers, and many other diseases.⁷⁾ A vast number of new ent-kaurane diterpenoids and their related compounds (kaurane and grayanane diterpenoids) were isolated from the methanol extract of these leaves. NMR and MS techniques were used to determine the structures of the ent-kauranes as ent-18-acetoxy-7β-hydroxykaur-16-en-15-one (1),¹¹⁾ ent-1α-acetoxy-7β,14α-dihydroxykaur-16-en-15-one (2), ent-18-acetoxy-7β,14α-dihydroxykaur-16-en-15-one (3),¹²⁾ ent-1α,14α-diacetoxy-7β-hydroxykaur-16-en-15-one (4), ent-1α,7β-diacetoxy-14α-hydroxykaur-16-en-15-one (5), ent-18-acetoxy-14α-hydroxykaur-16-en-15-one (6), ent-(16S)-18-acetoxy-7β-hydroxykauran-15-one (7),¹³⁾ ent-7β-acetoxy-11α-hydroxykaur-16-en-15-one (8), ent-18-acetoxy-11α-hydroxykaur-16-en-15-one (9), ent-11α-acetoxykaur-16-en-18-oic acid (10), ent-15α,18-dihydroxykaur-16-ene (11), ent-11α,18-diacetoxy-7β-hydroxykaur-16-en-15-one (12), ent-(16S)-1α,14α-diacetoxy-7β-hydroxy-17-methoxykauran-15-one (13),¹⁴⁾ ent-7β,18-dihydroxy-kaur-16-en-15-one (14),¹⁵⁾ ent-11α-acetoxy-7β-hydroxykaur-16-en-15-one (15),¹⁶⁾ ent-11α-acetoxykaur-16-en-18-ol (16), ent-11β-hydroxy-18-acetoxykaur-16-ene (17), ent-14α-hydroxy-18-acetoxykaur-16-ene (18), and ent-7β-hydroxy-18-acetoxykaur-16-ene (19)¹⁷⁾ (Fig. 1). In some examples (compounds 4–11), the circular dichroism (CD) method was used to resolve the absolute configurations of ent-kaurane compounds. An extraction of the whole plant with methanol yielded eight further new ent-kaurane diterpenoids, crotonkinins C–J (20–27).¹⁸⁾ A possible biosynthetic coupling of the corresponding precursors 14 and 1 gave two new ent-kaurane dimers crotonkinensins C (28) and D (29).¹⁹⁾ The co-occurrence of epimeric kaurane series and rearranged skeletons in C. tonkinensis was detected. The leaves yielded two new kaurane diterpenes, 14α-hydroxykaur-16-en-7-one (30) (crotonkinin Α) and 14α-acetoxy-17-formylkaur-15-en-18-ol (31) (crotonkinin B),²⁰⁾ and two new grayanane (rearranged ent-kaurane) diterpenoids, 7α,10α-epoxy-14β-hydroxygrayanane-1(5),16-dien-2,15-dione (crotonkinensin A) (32) and 7α,10α-epoxy-14β-hydroxygrayanane-1(2),16-dien-15-one (crotonkinensin B) (33).²¹⁾ The grayanane diterpenoids 32 and 33 comprise a 7α,10α-epoxy-14β-hydroxy-16-en-15-one structure present in the ent-kaurane diterpenoids in C. tonkinensis, suggesting the precursor role of these ent-kaurane diterpenoids in their biosynthesis.

Fig. 1. New Compounds from C. tonkinensis

2.2. The Genus Mallotus (Euphorbiaceae)

The genus Mallotus is one of the most diverse and rich genera of the Euphorbiaceae family in Vietnam. One hundred fifty Mallotus species are mainly distributed in tropical and sub-tropical regions in Asia, and the following 40 species have been found in Vietnam: M. anisopodus (GAGNEP.) AIRY-SHAW, M. apelta (LOUR.) MUELL.-ARG., M. barbatus MUELL.-ARG., M. canii THIN, M. chrysocarpus PAMPAN., M. chuyenii THIN, M. clellandii HOOK. f., M. contubernalis HANCE, M. cuneatus RIDL., M. muricatus (WIGHT) MUELL.-ARG., M. eberhardtii GAGNEP., M. esquirolii LEVL., M. floribundus (BLUME) MUELL.-ARG., M. glabriusculus (KURZ) PAX & HOFFM., M. hanheoensis THIN, M. hookerianus (SEEM.) MUELL.-ARG., M. kurzii, M. lanceolatus (GAGNEP.) AIRY-SHAW, M. luchenensis METC., M. macrostachyus (MIQ.) MUELL.-ARG., M. metcalfianus CROIZ., M. microcarpus PAX & HOFFM., M. mollissimus (GEISEL.) AIRY-SHAW, M. nanus AIRY-SHAW, M. oblongifolius (MIQ.) MUELL.-ARG., M. oreophilus MUELL.-ARG., M. pallidus (AIRY-SHAW) AIRY-SHAW, M. paniculatus (LAM.) MUELL.-ARG., M. peltatus (GEISEL.) MUELL.-ARG., M. philippensis (LAM.) MUELL.-ARG., M. phongnhaensis THIN & KIM THANH, M. pierrei (GAGNEP.) AIRY-SHAW, M. poilanei GAGNEP., M. repandus (WILLD.) MUELL.-ARG., M. resinosus (BLANCO) MERR., M. sathayensis THIN, M. spodocarpus AIRY-SHAW, M. thorelii GAGNEP., M. ustulatus (GAGNEP.) AIRY-SHAW, and M. yunnanensis PAX & HOFFM.^9,22) There are extensive medical records on the use of Mallotus species as medicinal plants in Vietnam and South-East Asian countries. M. apelta, M. barbatus, M. floribundus, M. glabriusculus, M. macrostachyus, M. oblongifolius, M. paniculatus, M. philippinensis, and M. poilanei are used to treat such diseases as gastrointestinal disorders, hepatic diseases, fever, and malaria.²²⁾ The leaves of M. mollissimus are used in the treatment of stomach cramps and together with the bark are used to cure ailments of the spleen. A recent review summarized the chemical and pharmacological studies of some Mallotus species in Vietnam through the year 2010.²²⁾ Triterpenoids, various types of flavonoids and phenolic compounds, and coumarins are common naturally occurring substances obtained from Mallotus species.

In continuation of the study of Mallotus species in Vietnam, two new megastigmane sulphonoglucosides, anisoposides A (34) and B (35), were isolated from the leaves of M. anisopodus.²³⁾ A new megastigmane glycoside, malloluchenoside (36), was also obtained from water-soluble fractions of a methanol extract from the leaves of M. luchenesis.²⁴⁾ Two new 2-C-β-D-glucopyranosyl benzoic acid derivatives, mallonanosides A (37) and B (38), were isolated from the methanol extract of the leaves of M. nanus.²⁵⁾ A new lignan dimer, bilariciresinol (39), was isolated from the leaves of M. philippensis.²⁶⁾ The methanol leaf extract of M. macrostachyus yielded two new cycloartanes, macrostachyosides A (40) and B (41).²⁷⁾ (2S)-Prenylflavanones and taraxerane triterpenoids were isolated from the leaves of M. mollissimus, including a pair of new diastereomeric prenylflavanones, (2″S)- and (2″R)-(2S)-5,7-dihydroxy-4′-methoxy-6-(2″-hydroxy-3″-methylbut-3-enyl)flavanones (42 R/S)²⁸⁾ (Fig. 2).

Fig. 2. New Compounds from Mallotus Species

2.3. The Genus Artemisia (Asteraceae, syn. Compositae)

The large Asteraceae (syn. Compositae) family comprises 1000 genera and 20000 species worldwide. The genus Artemisia is a member of the Asteraceae family, widely distributed in the warmer temperate zones of Europe, Asia, and North America. Artemisia comprises more than 500 species worldwide, with sixteen species described in the flora of Vietnam: A. absinthium L., A. annua L., A. apiacea HANCE ex WALP, A. campestris L., A. capillaris THUNB., A. carvifolia [BUCH.-HAM. ex ROXB.] BESS., A. dracunculus L., A. dubia var. longeracemosa forma tonkinen PAMP., A. indica WILLD., A. japonica THUNB., A. lactiflora WALL. ex DC., A. maritima L., A. palustris L., A. roxburghiana BESS., A. scoparia WADLST. & KIT., and A. vulgaris L.^9,29) These species are perennial, biennial, and annual herbs or small shrubs. Artemisia is an economically important plant genus because many Artemisia species have been known for their curative properties and have been used in the treatment of various ailments such as malaria, inflammation, cancer, and infections by fungi, bacteria, and viruses. A. annua and A. apiacea have been used as remedies for various fevers including malaria.⁷⁾ A. dubia WALL. ex BESSER is recorded as a remedy for the treatment of gastric problems, intestinal worms, and skin infections in China, India, Japan, and Thailand.^30,31) A. japonica is used in Vietnam and China to treat fever, headache, malaria, hypertension, and tuberculosis.⁹⁾ A. roxburghiana is a subshrub and is used to treat fever and intestinal worms.³²⁾ A. vulgaris has been used as an anti-inflammatory, an antispasmodic, an anthelmintic, and in the treatment of painful menstruation.⁷⁾ A huge interest has been observed in the genus Artemisia, with 260 Artemisia species investigated; their secondary metabolites and pharmacological activities have been summarized in several reviews.^33–36)

Sesquiterpene lactones eudesmanolides, guaianolides, and rarely, germacranolides, have been considered chemical makers of the Artemisia species.³⁵⁾ In contrast to the common occurrence of 5α,11βH-guaian-12,6α-olides and 11,13-guaiaen-12,6α-olides in many Artemisia species, 11αH-guaianolides were obtained from A. roxburghiana. Three new sesquiterpene lactones of this type, roxbughianin A (11-epiarborescin) (43), roxbughianin B (1β,4β,10β-trihydroxy-5α,11αH-guai-2-en-12,6α-olide) (44), and 11-epi-8α-hydroxyarborescin (45) were isolated from the leaves of A. roxburghiana^37,38) (Fig. 3). The configuration of roxbughianin A was determined using an X-ray crystallographic method³⁷⁾ (Fig. 4). Eudesmane sesquiterpenes are chemotaxonomic compounds of A. japonica; three new eudesmanes, named artemisidiols A–C (46–48) with an unusual 1α,6α,8α-oxygenated pattern, were obtained from the leaves of A. japonica in Vietnam.³⁹⁾ Oxygenated guaianolides and dicaffeoylquinic acids were obtained as main constituents from A. dubia WALL. ex BESS. in China and Korea, but its Vietnamese variety, A. dubia WALL. ex BESS. var. longeracemosa PAMP. forma tonkinensis PAMP., yielded natural 6-methoxy-1H-indole-3-methylcarboxylate (49) together with oleanene and ursane triterpenoids, acyl glycerols, and sterols⁴⁰⁾ (Fig. 3).

Fig. 3. New Compounds from Artemisia Species

2.4. The Genus Goniothalamus (Annonaceae)

The large Annonaceae family consists of 120 genera and more than 2000 species. The genus Goniothalamus comprises about 160 species of shrubs and trees in tropical and subtropical Asia. Goniothalamus species are used as medicines for abortion, anti-aging, body pains, rheumatism, skin complaints, typhoid fever, stomach ache, and fever.⁴¹⁾ Twenty-two Goniothalamus species have been recorded in Vietnam: G. albiflorus BAN, G. banii B. H. QUANG, R. K. CHOUDHARY & V. T. CHINH, G. chartaceus P. T. LI, G. chinensis MERR. & CHUN, G. donnaiensis FIN. & GAGNEP., G. elegans AST, G. expansus CRAIB, G. flagellistylus TAGANE & V. S. DANG, G. gabriacianus (BAILL.) AST, G. gracilipes BAN, G. leiocarpus (W. T. WANG) P. T. LI, G. macrocalyx BAN, G. multiovulatus AST, G. ninhianus BAN, G. takhtajanii BAN, G. tamirensis PIERRE ex FIN. & GAGNEP., G. tenuifolius KING, G. touranensis AST, G. undulatus RIDL., G. vietnamensis BAN, G. wightii HOOK. f. & THOMS., and G. yunnanensis W. T. WANG.⁹⁾ Phytochemical studies report the isolation of compounds from forty species of Goniothalamus out of the 160 known species.⁴¹⁾ Important constituents are styryllactones, alkaloids, and acetogenins. Styryllactones are divided into several subtypes such as styryl-pyrones, furano-pyrones, furano-furones, and pyrano-pyrones, whose chemistry and biological activities have been described in several reviews.^42,43) According to the size of the lactone rings, styryllactones are grouped into five-, six- and eight-membered ring lactones, or unusual styryllactones. Study of the leaves of G. tamirensis of Vietnam isolated a new alkaloid gonitamirine (50) together with goniotamiric acid (51) and 3,5-demethoxypiperolide (52).⁴⁴⁾ The latter two compounds, 51 and 52, were isolated for the first time from natural sources. Further work on the leaves of G. tamirensis yielded two new pyrano-pyrone styryllactones, (+)-8-epi-9-deoxygoniopypyrone (53) and (+)-9-deoxygoniopypyrone (54).⁴⁵⁾ Two new styryllactones, macrocalactone (55) and 3-deoxycardiobutanolide (56), were isolated from the fruits of G. macrocalyx⁴⁶⁾ (Fig. 5). Depending on the structures and physical appearance of the isolated styryllactones, their absolute configurations have been determined by X-ray crystallographic analysis or Mosher’s modified method.

Fig. 4. X-Ray Crystal Structure of 43

Fig. 5. New Compounds from Goniothalamus Species

2.5. The Genus Garcinia (Clusiaceae, syn. Guttiferae)

Plants of the Clusiaceae (syn. Guttiferae) family grow mainly in the tropics and number more than 1000 species. Garcinia is a large genus of polygamous trees or shrubs, distributed in tropical Asia, Africa, and Polynesia.⁴⁷⁾ More than fifteen known Garcinia species have been recorded in Vietnam, including G. cochinchinensis (LOUR.) CHOISY, G. cowa ROXB., G. fagraeoides A. CHEV, G. ferrea PIERRE, G. gaudichaudii PLANCH. & TRIANA, G. hanburyi HOOK. f., G. lanessanii PIERRE, G. mangostana L., G. merguensis WRIGHT, G. multiflora CHAMPION ex BENTHAM, G. oblongifolia CHAMPION ex BENTHAM, G. oligantha MERR., G. oliveri PIERRE, G. poilanei GAGNEP., G. schomburgkiana PIERRE, and G. tinctoria (CHOISY) W. F. WIGHT.⁹⁾ Species of the genus Garcinia have been used in traditional medicine to treat different illnesses and ailments such as vomiting, swelling, tapeworms, dysentery, chronic diarrhea, piles, pains, and heat complaints. The bark of G. cochinchinensis is a crude drug used in Vietnam to cure allergy, itches, and skin disease, while the buds are used for the treatment of threatened abortion.⁸⁾ The pericarp of G. mangostana is used in Southeast Asian countries for the treatment of abdominal pain, diarrhea, dysentery, infected wound, suppuration, and chronic ulcer.⁷⁾ The bark of G. oblongifolia is used for the treatment of allergy, itching, and hemoptysis.⁷⁾ G. schomburgkiana is used in the folk medicine of Vietnam for the treatment of cough and menstrual disturbances.⁶⁾ Xanthones and polyisoprenylated benzophenones are compounds of interest from the genus Garcinia because of their complex chemical structures and potent biological responses. New xanthones and a series of new polyisoprenylated benzophenones, named guttiferones or schomburgkianones, were isolated from the Garcinia species of Vietnam. New xanthones, 1-O-methylglobuxanthone (57) from the bark of G. vilersiana,⁴⁸⁾ merguenone (58) from the bark of G. merguensis,⁴⁹⁾ mangoxanthone (59) from the heartwood of G. mangostana,⁵⁰⁾ 6-O-demethyloliverixanthone (60) and schomburgxanthone (61) were isolated from the bark of G. schomburgkiana,⁵¹⁾ pedunxanthones A–C (62–64) from the bark and pedunxanthones D–F (65–67) from the pericarp of G. pedunculata,^52,53) oblongixanthones F–H (68–70) from the twigs of G. oblongifolia,⁵⁴⁾ planchoxanthone (71) from the pericarp of G. planchonii,⁵⁵⁾ and xanthochymusxanthones A (72) and B (73) from the bark of G. xanthochymus⁵⁶⁾ (Fig. 6). New guttiferones Q–S (74–76) were isolated from the pericarp of G. conchinchinensis,⁵⁷⁾ guttiferone I (77) from the stem bark of G. griffithii,⁵⁰⁾ and guttiferone T (78) from the bark of G. conchinchinensis.⁵⁸⁾ Guttiferone Q may be the biogenetic precursor of guttiferones R and S. The latter two may be synthesized from guttiferone Q by cyclization of the 3-methylbut-2-enyl side chain at C-8 to the oxygen atom at C-1 or by cyclization of the 4-methylpent-3-enyl group at C-5 to the oxygen atom at C-3.⁵⁷⁾ The fruits of G. schomburgkiana yielded eight new schomburgkianones A–H (79–86).⁵⁹⁾ The absolute configuration at C-40 of 78 and 79 was determined by Mosher’s modified method.^58,59) The absolute configuration of the bicyclo[3.3.1]nonane core of the schomburgkianones was assigned by comparison of their experimental electronic circular dichroism (ECD) spectra with those of related compounds.⁵⁹⁾ New non-isoprenylated benzophenones, benthaphenone (87) and 3′,6-dihydroxy-2,4,4′-trimethoxybenzophenone (88) were isolated from the bark of G. benthami and the heartwood of G. mangostana,^50,60) respectively (Fig. 7). Other new compounds include a megastigmane sulphoglycoside, friedolanostane, a friedocycloartane, protostane, and lanostane triterpenoids. The megastigmane 4-O-sulpho-β-D-glucopyranosyl abscisate (89) was isolated from the pericarp of G. mangostana.⁶¹⁾ The friedolanostanes (22Z,24E)-3β-acetoxy-9α-hydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid (90), (22Z,24E)-3β,9α-dihydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid (91), (22Z,24E)-9α-hydroxy-3-oxo-17,14-friedolanosta-14,22,24-trien-26-oic acid (92), (24E)-3-oxo-17,14-friedolanosta-8,14,24-trien-26-oic acid (93), (22Z,24E)-9α-hydroxy-3-oxo-17,13-friedolanosta-12,22,24-trien-26-oic acid (94), (22Z,24E)-3-oxo-17,14-friedolanosta-8,14,22,24-tetraen-26-oic acid (95), (22Z,24E)-9α-hydroxy-3-oxo-13α,30-cyclo-17,13-friedolanosta-22,24-dien-26-oic acid (96), and a friedocycloartane (22Z,24E)-3α-hydroxy-17,13-friedocycloarta-12,22,24-trien-26-oic acid (97) were isolated from the leaves and bark of G. benthami and from the bark of G. celebica.^60,62) New protostane (22Z,24E)-3-oxoprotosta-12,22,24-trien-26-oic acid (98) and lanostane triterpenoids garciferolides A (99) and B (100) were obtained from the bark of G. ferrea,⁶³⁾ while (E)-3β,9α-dihydroxylanosta-24-en-26-oic acid (101) and 3,23-dioxo-9,16-lanostadien-26-oic acid (102) were isolated from the bark of G. celebica.⁶²⁾ Five new prenylated depsidones, garcinisidone H (103) and oliveridepsidones A–D (104–107), were isolated from the bark of G. celebica and G. oliveri^62,64) (Fig. 8).

2.6. The Genus Ficus (Moraceae Family)

The genus Ficus belongs to the family Moraceae and is the largest genus within this family, with more than 800 species.⁶⁵⁾ Ficus species are deciduous trees, hemi-epiphyte shrubs, creepers, and climbers. Many Ficus species grow in the tropical and subtropical forests of both hemispheres and are used medicinally by local populations. The fruits, roots, and leaves of F. carica are used in traditional medicine to treat gastrointestinal, respiratory, and cardiovascular disorders, and as anti-inflammatory and antiplasmodic remedies.⁶⁵⁾ The leaves of F. drupacea are used to treat malaria, paragonimiasis, nasosinusitis, sinusitis, and anasarca. Leaf extracts of F. elastica are used as remedies for skin infections and skin allergies, and as a diuretic agent. The leaves, roots, and bark of F. microcarpa are used as herbs in Vietnam for perspiration, alleviating fever, and relieving pain. F. religiosa has been extensively used for a wide range of ailments of the central nervous system, endocrine system, gastrointestinal tract, reproductive system, respiratory system, and infectious disorders.⁶⁶⁾ F. deltoidea (Moraceae) is used in Malaysia to alleviate and heal ailments such as sores, wounds, and rheumatism, and as an after-birth tonic and an antidiabetic drug.⁶⁷⁾ There are about 511 Ficus species existing in Asia, Malaysia, the Pacific islands and Australia; 132 Ficus species occur in central and south America; and 112 Ficus species occur in Africa (South Sahara) and in Madagascar. The following 65 Ficus species have been listed in a Vietnam plant database: F. abelii MIQ., F. altissima BLUME, F. amplissima SM., F. annulata BLUME, F. ashday, F. aurata (MIQ.) MIQ., F. auricularia LOUR., F. balansae GAGNEP., F. benjamina L., F. binnendijkii MIQ., F. callophylla BLUME, F. callosa Willd., F. capillipes GAGNEP., F. chartacea (WALL. ex KURZ) WALL. ex KING, F. curtipes CORNER, F. drupacea THUNB., F. elastica ROXB. ex HORNEM, F. erecta THUNB., F. fistulosa REINW. ex BLUME, F. formosana MAXIM., F. fulva REINW. ex BLUME, F. geniculata KURZ, F. glaberrima BLUME, F. glandulifera (WALL. ex MIQ.) KING, F. henryi WARB. ex DIELS, F. heterophylla L. f., F. heteropleura BLUME, F. hirta VAHL., F. hispida L. f., F. ischnopoda MIQ., F. lacor BUCH.-HAM, F. laevis BLUME, F. langkokensis DRAKE, F. microcarpa L. f., F. nervosa B. HEYNE ex ROTH, F. obscura BLUME, F. oligodon MIQUEL, F. orthoneura H. LÉV. & VANIOT, F. pisocarpa BLUME, F. prostrata (WALL. ex MIQ.) BUCH.-HAM. ex MIQ., F. pumila L., F. racemosa L., F. religiosa L., F. retusa L., F. rhododendrifolia (MIQ.) MIQ., F. rumphii BLUME, F. sagittata VAHL, F. sarmentosa BUCH.-HAM., F. semicordata BUCH.-HAM., F. simplicissima LOUR., F. spathulifolia CORNER, F. stenophylla HEMSL., F. stricta MIQ., F. subcordata BLUME, F. subtecta CORNER, F. sumatrana MIQ., F. sundaica BLUME, F. superba MIQ., F. tinctoria G. FORST., F. tuphapensis DRAKE, F. variegata BLUME, F. variolosa LINDL. ex BENTH., F. vasculosa WALL. ex MIQ., F. villosa BLUME, and F. virens AITON.⁹⁾ Megastimane glycosides were isolated from the polar fractions of several Ficus plants of Vietnam. Fractionation of a methanol extract from the leaves of F. microcarpa yielded a new C-glucosylflavone, ficuflavoside (108), and a new megastigmane glycoside, ficumegasoside (109).⁶⁸⁾ Megastigmane dihydroalangionoside A (110) was also isolated for the first time from natural sources.⁶⁸⁾ The isolation of a megastigmane, sodium 4′-dihydrophaseate (111) was reported from F. drupacea, together with a new benzenediol glucoside, 1,4-di-O-β-glucopyranosyl-2-(1,1-dimethylporpenyl)benzene (112).⁶⁹⁾ Another new megastigmane glycoside, ficalloside (113) was isolated from a methanol extract of the leaves of F. callosa.⁷⁰⁾ New compounds obtained from F. elastica include sodium (1′S,6′R)-8-O-β-D-glucopyranosyl abscisate (114) and ficuselastic acid (115).⁷¹⁾ New ursane (3β-acetyl urs-14(15)-en-16-one (116)) and new lanostane (lanosterol-11-one acetate (117)) triterpenoids were obtained in an early work on F. fistulosa of Vietnam, along with five known triterpenoids⁷²⁾ (Fig. 9).

Fig. 6. New Xanthones from Garcinia Species

Fig. 7. New Benzophenones from Garcinia Species

Fig. 8. New Triterpenoids, Depsidones, and Megastigmane from Garcinia Species

Fig. 9. New Compounds from Ficus Species

3. Potential Candidates for Drug Discovery

3.1. Antimicrobial Activity

Staphylococcus aureus is a virulent pathogen that is currently the most common cause of infections in hospitalized patients. The increase in the resistance of S. aureus to antibiotics, coupled with its increasing prevalence as a nosocomial pathogen, is of major concern. Of eleven tested ent-kaurane diterpenoids from C. tonkinensis, compounds 1, 3, and 9 showed the lowest minimum inhibitory concentration (MIC) values at 500, 125, and 32 µg/mL against the methicillin-resistant Staphylococcus aureus (MRSA) strain. All three active diterpenoids possess an α,β-unsaturated cyclopentanone moiety in the D ring of the ent-kaurane skeleton.⁷³⁾

3.2. Antiplasmodial Activity

Ethanol and water extracts from the leaves of C. tonkinensis showed antiplasmodial activity against Plasmodium falciparum. Bioassay-guided fractionation of the ethanol extract resulted in the isolation of the active ent-kaurane 1. Compound 1 showed activity against the chloroquine-sensitive Plasmodium falciparum T966 strain with an IC₅₀ value of 16.47 µg/mL, and against the chloroquine-resistant Plasmodium falciparum K1 strain with an IC₅₀ value of 17.34 µg/mL.⁷⁴⁾

3.3. Antiinflammatory Activity

The dimeric transcription factor nuclear factor kappa B (NF-κB) activates the expression of genes involved in the inflammatory process. Therefore, NF-κB inhibitors are considered potential anti-inflammatory and anti-cancer compounds. Bioactivity-guided fractionation using NF-κB and Griess assay led to the isolation of new ent-kauranes 1–3 and ent-7β,14α-dihydroxykaur-16-en-15-one from the leaves of C. tonkinensis. They showed strong inhibitory activity of NF-κB activation (IC₅₀ values of 0.10±0.01, 0.42±0.07, 0.07±0.01, and 0.11±0.02 µM, respectively) and nitric oxide (NO) production (IC₅₀ values of 0.21±0.04, 0.47±0.03, 0.15±0.02, and 0.26±0.02 µM, respectively) in RAW264.7 cells.¹²⁾ Kuo et al. demonstrated the inhibition of new ent-kauranes 1, 2, 14, 30, ent-7β,14α-dihydroxykaur-16-en-15-one, ent-7β-hydroxykaur-16-en-15-one, and ent-kaur-16-en-15-one 18-oic acid from C. tonkinensis on NO production with IC₅₀ values <5 µM.²⁰⁾ Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is the major reactive oxygen species (ROS)-inducing enzyme in activated inflammatory cells. Compounds 1, 2, 14, ent-7β-hydroxykaur-16-en-15-one, and ent-7β,14α-dihydroxykaur-16-en-15-one potently inhibited NOX, with the maximum inhibition of NOX activity at 50 µM ranging from 20 to 29%.²⁰⁾ The strong inhibition of superoxide anion generation and elastase release by human neutrophiles in response to FMLP/CB by diterpenoids 1, 2, 12, and 32 with IC₅₀ values ranging from 1.12±0.06 to 2.64±0.12 µM demonstrated the potential use of these diterpenoids from C. tonkinensis in the development of antiinflammatory agents.¹⁸⁾ The activity of the inflammatory enzyme cyclooxygenase (COX-2) was also inhibited by grayanane diterpenes crotonkinensins A (32) and B (33), with IC₅₀ values of 7.14±0.2 and 5.49±0.2 µM, respectively.²¹⁾

3.4. Anticancer Activity

The cytotoxicity of ent-kaurane diterpenoids against various human cancer cell lines was tested as an anticancer primary screen. The importance of the 16-en-15-one moiety in the ent-kaurane D-ring was demonstrated in all cytotoxicity tests of the ent-kaurane diterpenoids and their related compounds from C. tonkinensis. The functional groups (hydroxyl or acetoxy groups) at C-7, C-11, C-14, and C-18 may modulate the potency of this cytotoxicity. New ent-kaurane 1 and ent-7β,14α-dihydroxykaur-16-en-15-one showed the highest potency against four human cancer cell lines, A459 (lung cancer), MCF-7 (breast adenocarcinoma), KB (epidermoid carcinoma), and KB-Vin (vinblastin-resistant KB cell line), with EC₅₀ values ranging from 0.61 to 1.45 µg/mL.²⁰⁾ New ent-kaurane diterpenoids 2, 3, 14, and ent-7β-hydroxykaur-16-en-15-one showed strong cytotoxicity against MCF-7, KB, and KB-Vin (EC₅₀<2 µg/mL). ent-Kaurane diterpenoids 1–4, 7, 8, and 12 showed cytotoxicity against LU (lung adenocarcinoma), RD (rhabdocarcoma), and Hep-G₂ (hepatocellular carcinoma) human cancer cell lines with IC₅₀<2 µg/mL.⁷⁵⁾ ent-Kaur-16-en-15-one diterpenoids (1–5, 7, 9, 14, 16, 30, 32), ent-7β,14α-dihydroxykaur-16-en-15-one, ent-18-hydroxykaur-16-en-15-one, and ent-1α,7β,14α-triacetoxykaur-16-en-15-one were also active against MCF-7, adryamicin-resistant MCF-7 (MCF-7/ADR), and against tamoxifen-resistant MCF-7 (MCF-7/TAM) human cancer cell lines. Compounds 1–5 and ent-7β,14α-dihydroxykaur-16-en-15-one showed the highest activity, with IC₅₀ values <5 µg/mL. The preferential cytotoxicity of 29 to MCF-7 and MCF-7/ADR as compared to MCF-7/TAM, and of 15 to MCF-7 as compared to MCF-7/ADR and MCF-7/TAM, was disclosed. Grayanane diterpenoid 32 showed cytotoxicity against the three human cell lines with IC₅₀ values ranging from 7.9 to 8.1 µg/mL, while its congener 33 did not show this inhibitory activity (IC₅₀>10 µg/mL).⁷⁶⁾ Crotonkinensin D (29) showed potent cytotoxic activity against MCF-7, MCF-7/TAM, MCF-7/ADR, and MDA-MB-231 breast human cancer cell lines with IC₅₀ values of 9.4±1.7, 2.6±0.9, 18.9±0.6, and 22.0±0.9 µM, respectively.¹⁸⁾ Human hepatocellular carcinoma is the most common type of liver cancer. The structural requirement of the 16-en-15-one moiety was observed in the cytotoxicity of ent-kauranoid against both human HepG2 and Hep3b cell lines. This cytotoxicity was closely correlated to apoptosis, as evidenced by concentration-dependent subG1 cell accumulation, and to increased annexin V expression. In addition, subtoxic concentrations of the active diterpenoids dramatically enhanced the sensitivity of human hepatocellular carcinoma cells to doxorubicin.⁷⁷⁾ AMP-activated protein kinase (AMPK) is a biologic sensor for cellular energy status that acts as a tumor suppressor and as a potential cancer therapeutic target. ent-Kaurane 1 blocked proliferation in dose- and time-dependent manners in human hepatocellular carcinoma SK-HEP1 cells. AMPK activation induced by 1 regulated cell viability and apoptosis. The study demonstrated that 1 is a novel AMPK activator, and that AMPK activation in SK-HEP1 cells is responsible for anticancer activity, including apoptosis.⁷⁸⁾ ent-Kauranes with a 15-oxo-16-ene moiety also induced the apoptosis of colorectal cancer cell lines, Caco-2 and LS180, and enhanced the generation of intracellular ROS in both cell types.⁷⁹⁾ The new cycloartanes 40 and 41 from M. macrostachyus showed cytotoxicity against the human cancer cell lines KB and LU-1 (lung adenocarcinoma) with IC₅₀ values ranging from 4.31±0.09 to 7.12±0.07 µg/mL.²⁷⁾ 3-Deoxycardiobutanolide (56) from G. macrocalyx was found to have potent cytotoxicity (IC₅₀ value of 0.09 µM) against HL-60 (human promyelocytic leukemia) cell lines, but no inhibitory activity against the KB cell line (IC₅₀>20 µM).⁴⁶⁾ Xanthones and polyisoprenylated benzophenones are mainly present in the genus Garcinia, and have been demonstrated to have significant cytotoxic activity in in vitro assay.⁴⁷⁾ 6-O-Demethyloliverixanthone (60) from G. schomburgkiana showed weak cytotoxic activity against HeLa (human cervical cancer) cell lines (IC₅₀ 16.7±1.9 µg/mL).⁵¹⁾ Pedunxanthone D (65) is an active compound against HeLa and NCI-H460 (human lung cancer) cells, with IC₅₀ values of 24.9±0.4 and 26.1±1.5 µg/mL, respectively.⁵³⁾ The new polyisoprenylated benzophenones guttiferones Q–S (74–76) were tested for three human cancer cell lines: MCF-7, HeLa, and NCI-H460. Guttiferone Q (74) showed strong activity, with IC₅₀ values of 2.74±0.12, 3.03±0.15, and 4.04±0.22 µg/mL, respectively, while guttiferones R (75) and S (76) were not active.⁵⁷⁾ Guttiferone T (78) showed weak activity, with IC₅₀ values of 19.88±0.14 and 14.31±0.94 µg/mL, respectively, against HeLa and MCF-7 human cancer cell lines.⁵⁸⁾

3.5. SIRT1 Inhibitory Activity

Silent information regulator two ortholog 1 (SIRT1) is a member of the sirtuin deacetylase family of enzymes that removes acetyl groups from lysine residues in histones and other proteins. It has been suggested that SIRT1 inhibitors might be beneficial in the treatment of cancer and neurodegenerative diseases. New ent-kauranes 1–5, 14, ent-7β,14α-dihydroxykaur-16-en-15-one, and ent-1α,7β,14α-triacetoxykaur-16-en-15-one from C. tonkinensis inhibited SIRT1 activity with IC₅₀ values ranging from 16.08±0.11 to 44.34±2.32 µg/mL, respectively.¹⁷⁾ The ent-kaur-16-en-15-one moiety has been shown to be the structural requirement for the inhibitory activity and functional groups at C-7 and C-11 that reinforce SIRT1 inhibitory activity.

3.6. Antioxidant Activity

Mallonanosides A (37) and B (38) from M. nanus showed antioxidant activities in an oxygen radical absorbance capacity (ORAC) test. The ORAC assay measures the oxidative degradation of the fluorescent molecule in vitro after being mixed with a free radical generator. Antioxidants are considered to protect the fluorescent molecule from oxidative generation. The peroxyl radical-scavenging activity of 37 was stronger than that of 38, and the increase of antiradical activity was explained by the presence of a hydroxyl group at C-4.²⁵⁾ Ficuflavoside (108) exhibited potent peroxyl radical-scavenging activity at the concentrations of 2.0 µM compared with the positive control, Trolox.⁶⁸⁾

3.7. Osteoblast Differentiation Assay

Direct stimulatory effect on osteoblast differentiation is an assay used to identify potential therapeutic molecules against bone diseases such as osteoporosis. New bone formation is primarily a function of the osteoblasts, agents that regulate bone formation, either by increasing the proliferation of cells in the osteoblastic lineage or inducing osteoblast differentiation. Bioactivity-guided fractionation using an in vitro osteoblast differentiation assay resulted in the isolation of ent-kaur-16-enes 16–18, and ent-7α-hydroxy-18-acetoxykaur-16-ene from C. tonkinensis. All ent-kaur-16-enes significantly increased alkaline phosphatase activity and osteoblastic gene promoter activity. Compounds 16–18 also increased the levels of alkaline phosphatase (ALP) and collagen type I alpha mRNA in C2C12 cells in a dose-dependent manner.¹⁷⁾ At concentrations of 2.67 µM, compounds 53 and 54 from G. taminensis significantly increased the growth of osteoblastic MC3T3-E1 cells and increased collagen synthesis, alkaline phosphatase activity, and nodule mineralization in the cells. 53 and 54 increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells.⁴⁵⁾

3.8. Antimycobacterial Activity

ent-Kaurane, kaurane, and grayanane diterpenoids from C. tonkinensis were subjected to an antituberculosis activity test against both susceptible and resistant strains of Mycobacterium tuberculosis. All of the compounds showed high to moderate activity against Mycobacterium. The highest antituberculosis activity was observed for ent-1α,7β,14α-triacetoxykaur-16-en-15-one, with MIC values of 0.78, 1.56, and 3.12–12.5 µg/mL against H37Ra, H37Rv and all other resistant strains of M. tuberculosis tested. ent-Kaurane diterpenoids with an α,β-unsaturated ketone in the D ring 1 (IC₅₀ 3.12–6.25 µg/mL), 2 (IC₅₀ 3.12–6.25 µg/mL), 4 (IC₅₀ 3.12–6.25 µg/mL), and 14 (IC₅₀ 1.56 µg/mL) showed high activities against Mycobacterium.⁸⁰⁾

3.9. Anti-diabetic Activity

Oblongixanthones G (69) and H (70) displayed potent α-glucosidase inhibitory activity (IC₅₀ 9.4±1.8 and 21.2±9.7 µM, respectively) but weak PTP1B (protein-tyrosine phosphatase 1B) inhibitory activity (IC₅₀ 94.8±12.0 and 82.4±6.8 µM, respectively). Oblongixanthone F (68) inhibited PTP1B with an IC₅₀ value of 33.1±4.7 µM and α-glucosidase with an IC₅₀ value of 36.7±20.0 µM. Xanthochymusxanthone B (73) exhibited strong inhibition towards PTP1B with an IC₅₀ value of 8.0±0.6 µM.⁵⁶⁾

4. Conclusion

Medicinal plants are rich sources of biologically active compounds. There are many unexplored medicinal plants in Vietnam that may offer a huge library for compounds of different structural types and biological potency in the process of drug discovery. Variations of skeleton architecture of such a compound library, through medicinal chemistry and chemical synthesis of analogs, greatly expands the complexity, diversity, and therapeutic efficacy of available natural compounds. The present review shows the importance of systematic phytochemical studies of plant materials, as well as multi-targeted activity tests of natural compounds from some popular groups of medicinal plants of Vietnam, as exemplified by the study of C. tonkinensis. With the advancement of separation and isolation techniques, and the inclusion of new bioassays, many new and/or biologically active compounds from medicinal plants in Vietnam are expected to be found.

Conflict of Interest

The authors declare no conflict of interest.

References

• 1) Salim A. A., Chin Y.-W., Kinghorn A. D., “Bioactive Molecules and Medicinal Plants,” eds. by Ramawat K. G., Mérillon J.-M., Springer, Berlin Heidelberg New York, 2008, pp. 1–24.
• 2) Blass B., “Basic Principles of Drug Discovery and Development,” 1st edition, Academic Press, Amsterdam, 2015.
• 3) Yuan H., Ma Q., Ye L., Piao G., Molecules, 21, 559 (2016).
• 4) David B., Wolfender J.-L., Dias D. A., Phytochem. Rev., 14, 299–315 (2015).
• 5) Nguyen V. H., “The Annonaceae family, Chemistry and Biological Activity of Desmos rostrata, Goniothalamus tamirensis, Fissistigma villosissimum,” Vol. 1, Publishing House Natural Science and Technology, Hanoi, 2011, p. 1.
• 6) Pham H. H., “The Flora of Vietnam,” Youth Publishing House, Ho Chi Minh City, 1999.
• 7) Do T. L., “Medicinal Plants and Herbal Remedies of Vietnam,” Publishing House Medicine, Ho Chi Minh City, 1999.
• 8) Vo V. C., “Dictionary of Vietnamese Medicinal Plants,” Publishing House Medicine, Ho Chi Minh City, 1997.
• 9) Vietnam Plant Data Center.: ‹www.botanyvn.com›.
• 10) Salatino A., Faria Salatino M. L., Negri G., J. Braz. Chem. Soc., 18, 11–33 (2007).
• 11) Son P. T., Giang P. M., Taylor W. C., Aust. J. Chem., 53, 1003–1005 (2000).
• 12) Giang P. M., Jin H. Z., Son P. T., Lee J. H., Hong Y. S., Lee J. J., J. Nat. Prod., 66, 1217–1220 (2003).
• 13) Giang P. M., Son P. T., Lee J. J., Otsuka H., Chem. Pharm. Bull., 52, 879–882 (2004).
• 14) Giang P. M., Son P. T., Hamada Y., Otsuka H., Chem. Pharm. Bull., 53, 296–300 (2005).
• 15) Minh P. T. H., Ngoc P. H., Taylor W. C., Cuong N. M., Fitoterapia, 75, 552–556 (2004).
• 16) Dao T. T., Le T. V. T., Nguyen P. H., Pham T. T., Pham T. H. M., Woo E. R., Lee K. Y., Oh W. K., Planta Med., 76, 1011–1014 (2010).
• 17) Dao T. T., Lee K. Y., Jeong H. M., Nguyen P. H., Tran T. L., Phuong T. T., Nguyen B. T., Oh W. K., J. Nat. Prod., 74, 2526–2531 (2011).
• 18) Kuo P.-C., Yang M.-L., Hwang T.-L., Lai Y.-Y., Li Y.-C., Thang T. D., Wu T.-S., J. Nat. Prod., 76, 230–236 (2013).
• 19) Thuong P. T., Pham T. H. M., Le T. V. T., Dao T. T., Dang T. T., Nguyen Q. T., Oh W. K., Bioorg. Med. Chem. Lett., 22, 1122–1124 (2012).
• 20) Kuo P.-C., Shen Y.-C., Yang M.-L., Wang S.-H., Thang T. D., Dung N. X., Chiang P.-C., Lee K.-H., Lee E.-J., Wu T.-S., J. Nat. Prod., 70, 1906–1909 (2007).
• 21) Phuong T. T., Dao T. T., Pham T. H. M., Nguyen P. H., Le T. V. T., Lee K. Y., Oh W. K., J. Nat. Prod., 72, 2040–2042 (2009).
• 22) Rivière C., Hong V. N. T., Hong Q. T., Chataigné G., Hoai N. N., Dejaegher B., Tistaert C., Kim T. N. T., Heyden Y. V., Van M. C., Quetin-Leclercq J., Phytochem. Rev., 9, 217–253 (2010).
• 23) Phan V. K., Nguyen T. M., Minh C. V., Nguyen H. K., Nguyen H. D., Nguyen P. T., Nguyen X. C., Nguyen H. N., Nguyen X. N., Heyden Y. V., Quetin-Leclercq J., Kim G. N., Jang H. D., Kim Y. H., Arch. Pharm. Res., 33, 203–208 (2010).
• 24) Minh C. V., Phan N. H. T., Thuy D. T. T., Thao N. P., Dang N. H., Kiem P. V., Heyden Y. V., Quetin-Leclercq J., VAST Proceedings, 294–300 (2008).
• 25) Mai N. T., Cuong N. X., Thao N. P., Nam N. H., Khoi N. H., Minh C. V., Heyden Y. V., Thuan N. T., Tuyen N. V., Quetin-Leclercq J., Kiem P. V., Nat. Prod. Commun., 5, 423–426 (2010).
• 26) Van Minh C., Thanh N. T., Quang T. H., Cuong N. X., Thin N. N., Nam N. H., Heyden Y. V., Quetin-Leclercq J., Van Kiem P., Nat. Prod. Commun., 4, 889–892 (2009).
• 27) Nam N. H., Kiem P. V., Ban N. K., Thao N. P., Nhiem N. X., Cuong N. X., Tistaert C., Dejaegher B., Heyden Y. V., Quetin-Leclercq J., Thao D. T., Minh C. V., Phytochem. Lett., 4, 348–352 (2011).
• 28) Phan M. G., Vu M. T., Kawakami S., Otsuka H., Biochem. Syst. Ecol., 73, 22–25 (2017).
• 29) Tariku Y., Hymete A., Hailu A., Rohloff J., Chem. Biodivers., 7, 1009–1018 (2010).
• 30) Ashraf M., Hayat M. Q., Jabeen S., Shaheen N., Khan M. A., Yasmin G., J. Med. Plants Res., 4, 112–119 (2010).
• 31) Hayat M. Q., Khan M. A., Ashraf M., Jabeen S., Ethnobot. Res. App., 7, 147–162 (2009).
• 32) Hayat M. Q., Ashraf M., Khan M. A., Yasmin G., Shaheen N., Jabeen S., Afr. J. Biotechnol., 8, 6561–6568 (2009).
• 33) Bora K. S., Sharma A., Pharm. Biol., 49, 101–109 (2011).
• 34) Ivanescu B., Miron A., Corciova A., J. Anal. Methods Chem., 2015, 247685 (2015).
• 35) Abad M. J., Bedoya L. M., Apaza L., Bermejo P., Molecules, 17, 2542–2566 (2012).
• 36) Martínez M. J. A., Olmo L. M. B. D., Benito P. B., “Studies in Natural Products Chemistry,” Vol. 37, ed. by Atta-ur-Rhaman, Elsevier, Amsterdam, 2012, pp. 43–65
• 37) Phan M. G., Tran T. T. N., Phan T. S., Otsuka H., Matsunami K., Biochem. Syst. Ecol., 45, 115–119 (2012).
• 38) Giang P. M., Nhan T. T. T., Son P. T., Otsuka H., Matsunami K., Nat. Prod. Res., 27, 1856–1858 (2013).
• 39) Giang P. M., Binh N. T., Matsunami K., Son P. T., Nat. Prod. Res., 28, 631–635 (2014).
• 40) Phan M. G., Tran T. T. N., Truong T. T. C., Phan T. S., Matsunami K., Chem. Nat. Compd., 51, 378–380 (2015).
• 41) Aslam M. S., Ahmad M. S., Mamat A. S., Ahmad M. Z., Salam F., Recent Advances in Biology and Medicine, 2, 34–47 (2016).
• 42) Blázquez M. A., Bermejo A., Zafra-Polo M. C., Cortes D., Phytochem. Anal., 10, 161–170 (1999).
• 43) Choo C.-Y., Abdullah N., Diederich M., Phytochem. Rev., 13, 835–851 (2014).
• 44) Tran D. T., Mai H. D. T., Pham V. C., Nguyen V. H., Litaudon M., Guéritte F., Nguyen Q. V., Tran T. A., Chau V. M., Phytochem. Lett., 6, 79–83 (2013).
• 45) Tai B. H., Huyen V. T., Huong T. T., Nhiem N. X., Choi E. M., Kim J. A., Long P. Q., Cuong N. M., Kim Y. H., Chem. Pharm. Bull., 58, 521–525 (2010).
• 46) Trieu Q. H., Mai H. D., Pham V. C., Litaudon M., Gueritte F., Retailleau P., Schmitz-Afonso I., Gimello O., Nguyen V. H., Chau V. M., Nat. Prod. Commun., 9, 495–498 (2014).
• 47) Kumar S., Sharma S., Chattopadhyay S. K., Fitoterapia, 89, 86–125 (2013).
• 48) Nguyen L.-H. D., Harrison L. J., Phytochemistry, 53, 111–114 (2000).
• 49) Nguyen L.-H. D., Vo H. T., Pham H. D., Connolly J. D., Harrison L. J., Phytochemistry, 63, 467–470 (2003).
• 50) Nguyen L.-H., Venkatraman G., Sim K. Y., Harrison L. J., Phytochemistry, 66, 1718–1723 (2005).
• 51) Vo H. T., Nguyen N.-T. T., Nguyen H. T., Do K. Q., Connolly J. D., Maas G., Heilmann J., Werz U. R., Pham H. D., Nguyen L.-H. D., Phytochem. Lett., 5, 553–557 (2012).
• 52) Vo H. T., Nguyen N.-T. T., Maas G., Werz U. R., Pham H. D., Nguyen L.-H. D., Phytochem. Lett., 5, 766–769 (2012).
• 53) Vo H. T., Ngo N. T. N., Bui T. Q., Pham H. D., Nguyen L.-H. D., Phytochem. Lett., 13, 119–122 (2015).
• 54) Trinh B. T. D., Quach T. T. T., Bui D. N., Staerk D., Nguyen L.-H. D., Jäger A. K., Fitoterapia, 118, 126–131 (2017).
• 55) Trinh D. H., Ha L. D., Tran P. T., Nguyen L.-H. D., Nat. Prod. Commun., 9, 1737–1740 (2014).
• 56) Nguyen C. N., Trinh B. T. D., Tran T. B., Nguyen L.-T. T., Jäger A. K., Nguyen L.-H. D., Bioorg. Med. Chem. Lett., 27, 3301–3304 (2017).
• 57) Nguyen H. D., Trinh B. T. D., Nguyen L.-H. D., Phytochem. Lett., 4, 129–133 (2011).
• 58) Trinh B. T. D., Nguyen N.-T. T., Ngo N. T. N., Tran P. T., Nguyen L.-T. T., Nguyen L.-H. D., Phytochem. Lett., 6, 224–227 (2013).
• 59) Le D. H., Nishimura K., Takenaka Y., Mizushina Y., Tanahashi T., J. Nat. Prod., 79, 1798–1807 (2016).
• 60) Nguyen H. D., Trinh B. T. D., Tran Q. N., Nguyen H. D., Pham H. D., Hansen P. E., Duus F., Connolly J. D., Nguyen L.-H. D., Phytochemistry, 72, 290–295 (2011).
• 61) Tran T. H., Le H. T., Tran T. M., Nguyen T. A., Pham T. B., Nguyen T. D., Nat. Prod. Res., 30, 1598–1604 (2016).
• 62) Bui T. Q., Bui A. T., Nguyen K. T., Nguyen V. T., Trinh B. T. D., Nguyen L.-H. D., Tetrahedron Lett., 57, 2524–2529 (2016).
• 63) Bui D. A., Vu M. K., Nguyen H. D., Nguyen L.-T. T., Dang S. V., Nguyen L.-H. D., Phytochem. Lett., 10, 123–126 (2014).
• 64) Ha L. D., Hansen P. E., Duus F., Pham H. D., Nguyen L.-H. D., Magn. Reson. Chem., 50, 242–245 (2012).
• 65) Mawa S., Husain K., Jantan I., Evidence-Based Comp. Alt. Med., 2013, 974256 (2013).
• 66) Singh D., Singh B., Goel R. K., J. Ethnopharmacol., 134, 565–583 (2011).
• 67) Bunawan H., Amin N. M., Bunawan S. N., Baharum S. N., Noor N. M., Evidence-Based Compl. Alt. Med., 2014, 902734 (2014).
• 68) Kiem P. V., Cuong N. X., Nhiem N. X., Thu V. K., Ban N. K., Minh C. V., Tai B. H., Hai T. N., Lee S. H., Jang H. D., Kim Y. H., Bioorg. Med. Chem. Lett., 21, 633–637 (2011).
• 69) Kiem P. V., Minh C. V., Nhiem N. X., Yen P. H., Anh H. L. T., Cuong N. X., Tai B. H., Quang T. H., Hai T. N., Kim S. H., Kwon S.-U., Lee Y.-M., Kim Y. H., Bull. Korean Chem. Soc., 34, 263 (2013).
• 70) Van Kiem P., Cuong N. X., Nhiem N. X., Hang D. T., Nam N. H., Ban N. K., Minh C. V., Bing Z., Jang H. D., Kim Y. H., Nat. Prod. Commun., 6, 159–162 (2011).
• 71) Kiem P. V., Minh C. V., Nhiem N. X., Tai B. H., Quang T. H., Anh H. L. T., Cuong N. X., Hai T. N., Kim S. H., Kim J. K., Jang H.-D., Kim Y. H., Bull. Korean Chem. Soc., 33, 3461–3464 (2012).
• 72) Tuyen N. V., Kim D. S. H. L., Fong H. S., Soejarto D. D., Khanh T.-C., Tri M. V., Xuan L. T., Phytochemistry, 50, 467–469 (1998).
• 73) Phan M. G., Phan T. S., Matsunami K., Otsuka H., J. Nat. Med., 60, 93–95 (2006).
• 74) Phan T. S., Le H. T., Phan M. G., Vietnam J. Chem., 40, 53–57 (2002).
• 75) Phan M. G., Phan T. S., Vietnam Pharm. J., 51, 24–27 (2011).
• 76) Thuong P. T., Tuan D. T., Minh P. T. H., Thu N. T. B., Khoi N. M., Pharmacogn. J. (Vietnam), 16, 9–19 (2011).
• 77) Pham M. Q., Iscache A. L., Pham Q. L., Gairin J. E., Fundam. Clin. Pharmacol., 30, 137–146 (2016).
• 78) Thuong P. T., Khoi N. M., Ohta S., Shiota S., Kanta H., Takeuchi K., Ito F., Anticancer. Agents Med. Chem., 14, 1051–1061 (2014).
• 79) Sul Y. H., Lee M. S., Cha E. Y., Thuong P. T., Khoi N. M., Song I. S., Biol. Pharm. Bull., 36, 158–164 (2013).
• 80) Jang W. S., Jyoti M. A., Kim S., Nam K.-W., Ha T. K. Q., Oh W. K., Song H.-Y., J. Nat. Med., 70, 127–132 (2016).