Phytoconstituents of Genus Micromelum and Their Bioactivity

Abstract

The genus Micromelum belongs to the Rutaceae family. As its rich bioactive constituents its stems, flowers, leaves, and roots have been used in traditional medicine, for the treatment of various diseases from ancient time. Phytochemically, many bioactive compounds, including coumarins, polyoxygenated flavonoids, phenylpropanoic acid derivatives, quinolone alkaloids, and also carbazole alkaloids, have been reported as secondary metabolites of the Micromelum spp. including many new compounds. Therefore, Micromelum spp. are considered potential for drug leads. In this article, we present an overview of secondary metabolites isolated from genus Micromelum and their bioactivities that have been reported between 1982 and 2019.

Keywords

Rutaceae coumarins flavonoids quinolone and carbazole alkaloids

Introduction to Chemical Constituents of Genus Mocromelum and Their Bioactivity

Micromelum spp. (Rutaceae) consist of 9 species found mostly in Samoa, Fiji, and Tonga islands, Australia, Southeast Asia, southern China, Ceylon, northeastern India, and West Pakistan.^1,2 Micromelum spp. are known for being rich in coumarins such as the 6- and 8-prenylated coumarins. In addition, the carbazole alkaloids, dihydrocinnamic acid derivatives, and flavonoids have been isolated from it.^3,4 The leaves and stems of Micromelum species have been found to contain coumarins, phenylpropanoic acid derivatives, polyoxygenated flavonoids, and also alkaloids.^5,6 The following Micromelum species have been well investigated due to their pharmaceutical properties.

M. integerrimum is a tree that grows up to 8 m high. Its young parts have rust-colored pubescent. It usually grows in moist mountain forests, maritime thickets in sandy soil; near sea level to 2000 m and is widely distributed in China, Bhutan, Cambodia, India, Laos, Myanmar, Nepal, Thailand, and Vietnam.⁷ M. integerrimum is highly diversified for its secondary metabolites, and apart from acridone and carbazole alkaloids, a variety of coumarin derivatives, especially 6,7-di and 7,8-disubstituted coumarin core structures, having at least a prenyl unit have been isolated. Naturally occurring coumarin derivatives from Micromelum spp. exhibit a variety of biological activities including anti-corpulence, cytotoxicity, anti-platelet, and antimutagenicity.³

M. minutum is a small spineless tree that can reach up to 3 m in height. It is widely distributed in Southeast Asia and in Pacific islands. The stems, flowers, leaves, and roots are used pharmaceutically for a variety of indications.^8,9 The plant is known to contain coumarins, some of which are active compounds showing strong cytotoxic activities. The leaves are traditionally used to treat fever and giddiness. The poultice of the boiled roots is used for ague.¹⁰ In Indochina, the roasted and crushed leaves are rubbed to skin irritated by scabies and are considered to be emmenagogues.¹¹ Previous phytochemical investigations on the different parts of M. minutum have showed the presence of coumarins, triterpenes, alkaloids, and phenylpropanoids.¹²

M. falcatum is a tree of 1-3 m high and its leaflet blades are alternate, ovate to lanceolate, in equilateral. Flowers are ellipsoid or broad in bud. Petals are white, oblong, outside glabrous, or pubescent. Fruits are ellipsoid to ovoid, 1- or 2-seeded. Its flowering period is from January to April. It is usually found in the mountain area at heights below 1200 m in China, Cambodia, Laos, Myanmar, Thailand, and Vietnam.¹³ Its leaves and roots are used for treating infected wounds, odynolysis, rheumatism, muscular atrophy, and insect bites.^4,14 M. falcatum has been found to contain several coumarins, such as 7-oxygenated coumarins, dihydrocinnamic acid derivatives, the dimeric indole alkaloid (yuehchukene), the carbazole alkaloid, 5,6-pyranoglycozoline, the 6-prenylated coumarin, micromelin, and the 8-prenylated coumarins, phebalosin and murpanidin.^6,15,16 The dimeric indole alkaloid yuehchukene was found to have potent anti-implantation activity.¹⁷

M. compressum is a tree described as unarmed and glabrous. Its leaves are odd-pinnate, the leaflets are alternate, and the fruits are ovoid. Phytochemical efforts on the CH₂Cl₂-methanol extract of M. compressum have resulted in the isolation and identification of 3 polymethoxylated flavones.¹

M. hirsutum is a tree of up to 10 m height with greenish-yellow flowers and aromatic leaves. It is widely distributed in peninsular Malaysia (Melaka and Pahang northward), Andaman Islands, Myanmar, Laos, Thailand, and Vietnam.¹⁸ In 2010, Rodphukdeekul research group investigated antitumor activity of the dichloromethane extract from branches of M. hirsutum on human B lymphoma cells, Ramos. The result demonstrated that the extract has antitumor potential against B lymphoma.¹⁹ In Myanmar its leaves are widely used as spices in curries. Phytochemial analysis of this species has reported the presence of many carbazole alkaloids, as well as the γ-lactone compounds.¹⁸

M. glanduliferum is a tropical or subtropical small tree found in Thailand. Coumarins and some carbazole alkaloids compounds, such as osthol, phebalosin, minumicrolin, murrangatin, murralongin, micormarin A, microminutinin, micromelin, and 2,7-dihydroxy-3-formyl-1-(30-methyl-20-butenyl)carbazole and 7-methoxy heptaphylline, were reported from the roots of M. glanduliferum.²⁰

The chemical analysis of leaves and stems of M. zeylanicum has reported an oxazole alkaloid, O-methylhalfordinol, a coumarin, micromelin, and a flavone, 5-hydroxy-3,3ʹ,4ʹ,7-pentamethoxyflavone. In addition, the stems contained 6-formyl-7-methoxycoumarin, and the leaves contained the carbazole alkaloid, koenigine, and p-sitosterol.²¹

In this review the articles were collected from 1982 to 2019. The main purpose of this article was to evaluate the diversity of secondary metabolites isolated from Micromelum spp. in order to provide a complete reference of the diverse secondary metabolites from Micromelum spp. To the best of our knowledge this is the first review about secondary metabolites isolated from genus Micromelum.

Phytochemical Aspects of Micromelum Spp. and Their Tested Bioactivities

Coumarins

Coumarins are highly active biological substances and major secondary metabolites isolated from Micromelum spp. They are widely used in medicine, perfumes, cosmetics, and laser dyes.⁶ Coumarins have antioxidant activity and they preserve the levels of other antioxidants in human plasma. Coumarins also inhibited lipid peroxidation and increased the activity of antioxidants, superoxide dismutase, and catalase.²² Many bioactive coumarins have been reported from genus Micromelum, and the basic core coumarin compound, umbelliferone (1), was isolated from the roots of M. minutum.⁸ Scopoletin compound 7-hydroxy-6-methoxy-2H-chromen-2-one (2) was isolated the fruits of M. minutum ²³ and 6-hydroxy-7-methoxy-2H-chromen-2-one (3) was isolated from the stems and leaves of M. integerrimum.²⁴ Another coumarin, 6-formyl-7-methoxycoumarin (4), was isolated from the leaves and stems of M. zeylanicum.²¹ 7-Methoxyprenylated coumarin, osthenon (5), and osthol (6) were isolated from the roots of M. minutum.⁸ Microfalcrin (7) was isolated from the leaves of M. falcatum.¹⁶ This compound (7) was also found in M. minutum ⁸ (Figure 1).

Figure 1

Coumarins from Micromelum minutum, M. integerrimum, M. falcatum, and M. zeylanicum.

One-prenylated coumarins named micromarin-F (8), -G (9), and -H (10) were isolated from the stems of M. minutum.²⁵ The compound murralongin-1 (11) was isolated from the roots of M. minutum.⁸ Murralongin-2 (12) and murralonginol (13) were isolated from the fruits of M. minutum.^23,26 7-Oxygenated coumarins, phebalosin (14), murrangatin (15), murrangatin acetate (16), murracarpin (17), and minumicrolin (18) were isolated from the roots of M. minutum ⁸ (Figure 1). Microminutin (19) was isolated from the acetone extract of the stems of M. minutum.²⁵ Some coumarins, such as 7-methoxy-8-(4′-methyl-3′-furanyl)coumarin (20), microminutin B (21), microminutin C (22), and micromeloside A (23), were isolated from the finely powdered fruits of M. falcatum ⁴ (Figure 2). In 2014, Kouloura et al reported microcoumaririn (24) from the leaves of M. falcatum. The anti-inflammatory properties of compounds (24, 32) were evaluated by measuring the inhibition of the proinflammatory mediator nuclear factor kappa B induction and nitric oxide (NO) production but these 2 compounds did not show any inhibition.¹⁶

Figure 2

Coumarins isolated from Micromelum falcatum.

Micromelin or 7-methoxy-6-((1R,2R,5R)−5-methyl-4-oxo-3,6-dioxabicyclo[3.1.0]hexan-2-yl)−2H-chromen-2-one (25) was isolated from the fruits of M. minutum.²³ This compound is common to all species of Micromelum so far examined and can perhaps be considered as a chemotaxonomic marker for the genus.²⁷ The compound acetyldihydromicromelin A (26) was isolated from the aerial parts of M. minutum.²⁶ One-prenylated coumarin, namely hydramicromelin D (27), was isolated from the twigs of M. integerrimum.³ Hopeyhopol (28) and marmesin (29) were isolated from the whole plants of M. minutum.²⁸ (−) Decursinol (30) was isolated from the finely powdered fruits of M. falcatum.⁴ One-prenylated coumarins named micromarin-A (31), -B (32), and -C (33) were isolated from the seeds of M. minutum ²² and fruits of M. falcatum ¹⁶ (Figure 3).

Figure 3

Some coumarins isolated from Micromelum integerrimum and M. minutum.

Ester coumarinoids, (3S,4S)−3,4-dihydroxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-ethylenebutyl 3-methylbutanoate (34), (3R,4S)−3,4-dihydroxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-methylenebutyl-3-methylbutanoate (35), and 3-hydroxy-4-methoxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-methylenebutyl-3-ethylbutanoate (36), were isolated from the finely powdered fruits of M. falcatum ^4,16 (Figure 4). Another ester coumarin, 7-methoxy-8-(2-hydroxymethyl-1-O-isovaleryl-4-butenyl) coumarin (37), was isolated from the stem bark of M. falcatum.²⁹

Figure 4

Coumarins from Micromelum minutum and M. falcatum.

Murralonginol isovalerate-1 (38) was isolated from the stems of M. minutum.²³ Toxicity of compound (37) isolated from M. falcatum was tested against brine shrimp larvae using a 96-well plate assay and the compound (37) exhibited an LC₅₀ value of 6.8 µM, indicating that it was a potent toxic natural product and its in vitro antiproliferative activities against lung cancer (HvEvc) cell lines by the MTT method, and (37) displayed moderate activity against the HvEvc cell line with IC₅₀ value of 35.7.²⁹ Two-prenylated coumarins, murralonginol isovalerate-2 (39), minutuminolate (40), and 7-demethylmurralonginolisovalerate (41), were isolated from the fruits and roots of M. minutum ^8,23 (Figure 4). Micromarinate (42) was isolated from the EtOAc extract fruits of M. falcatum ⁴ (Figure 4).

Five other geranylcoumarins, such as 8-hydroxyisocapnolactone-2ʹ,3ʹ-diol (43), isolated from M. minutum have in vitro antiplasmodial activity against Plasmodium falciparum FCR-3 and D-10 strains with IC₅₀ values of 6.39 µg/mL (16.99 µM) and 24.23 mg/mL (64.45 µM), respectively.¹⁰ 8-methoxycapnolactone (44), 3″,4″-dihydrocapnolactone (45), 2ʹ,3ʹ epoxyisocapnolactone (46), 8-hydroxy-3″,4″-dihydrocapnolactone-2ʹ,3ʹ-diol (47), and 8,4-dihydroxy-3,4-dihydrocapnolactone-2,3-diol (48) were isolated from the leaves of M. minutum ^10,11,30 (Figure 5). These coumarins contained a lactone ring in their structure. In 2009, Ratna et al reported the cytotoxicity of these lactone coumarins on T-lymphoblastic leukemia (CEM-SS), promyeolocytic leukemia (HL60), cervical cancer (HeLa), and liver cancer (HepG2) cell lines. Among the tested compounds, (43) showed the most active with IC₅₀ values of 2.9, 2.5, 6.9, and 5.9 µg/mL, respectively.¹¹ In 2014, the same group investigated the cytotoxic activity of compound (43) on MCF-7 and T47D cells. The results showed IC₅₀ values of 8 µg/mL (21.2 µM) and 4 µg/mL (10.6 µM) respectively.³¹

Figure 5

Coumarins from the Micromelum minutum.

Two monoterpene coumarins, minutin A (49) and minutin B (50), were isolated from the leaves of M. minutum (Figure 5) and their cytotoxic activity against Leishmania major and cancer cells were already studied. It has been reported that minutin B (50) has strong cytotoxic activity against the cancer cell lines such as SBC3, A549, K562, and K562/ADM with IC₅₀ values of 8.8, 10.1, 16.9, and 10.1 µM, respectively.³²

The 7-methoxylated coumarin, micromelosidester (51), was isolated from the leaves of M. falcatum.¹⁶ Two compounds microminutinin (52) and 6-methoxymicrominutinin (53) were isolated from the leaves of M. falcatum.⁴ These 2 compounds are different from other compounds shown previously, because the prenyl attached on coumarin core forms a bicyclic structure. Other 2-prenylated coumarins named integerrimelin (54), (1R,3R,4R,6S)−4-(7-Methoxy-2-oxo-2H-chromen-6-yl)−1-methyl-3,6-dioxabicyclo[3.1.0]hexan-2-yl acetate (55), and scopolin (56) were isolated from the twigs, stems, and leaves of M. integerrimum.^3,24,33 A glycoside coumarin 7-methoxy-8-(1-hydroxy-2-O-β-glucopyranosyl-3-methyl-4-butene-1-yl) coumarin (57) was isolated from the stem bark of M. falcatum.²⁹ Another coumarin, micromelumoside D (58), was isolated from the aerial portions of M. minutum ⁶ (Figure 6).

Figure 6

Coumarins from the Micromelum minutum, M. integerrimum, and M. falcatum.

In 2018, Kassim et al reported a lignan sesamin (118) (Figure 7) together with 3 couramins, hydramicromelinin (59), micromelinin (60), and 1-O-β-D-glucopyranosylmarmesin (61) (Figure 8) from M. minutum methanol bark extract. Of the reported compounds, the ORAC measurements of compounds 59 and 118 showed potent antioxidant activity with the values of 5539 and 4031 µmol TE/g, respectively.³⁴

Figure 7

Miscellaneous compounds from the Micromelum integerrimum, M. hirsutum, M. minutum, and M. falcatum.

Figure 8

Coumarins from the Micromelum minutum.

Alkaloids

Alkaloids have inspired the development of several antibacterial drugs through the synthesis of quinine serendipitously yielding the quinolones, structural alteration of azomycin yielding metronidazole, and working with the quinoline scaffold yielding bedaquiline. In other drugs, alkaloids are present as scaffold substructures, eg linezolid and trimethoprim. Alkaloids remain the focus of much research. Their development as antibacterial drugs pursued within academia, industry, and jointventures.³⁵ A large number of carbazole alkaloids have been isolated from higher plants of the genera Murraya, Glycosmis, Micromelum, and Clausena, all belonging to the family rutaceae.^36,37

The quinoldione alkaloids 2-(3-hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (62) and 3-hydroxy-1-methyl-3-(2-oxopropyl)quinoline-2,4(1H,3H)-dione (63) along with 2 quinolinone alkaloids N-methylflindersine (64), 4-hydroxy-3-methoxy-1-methyl-2(1 H)-quinolinone (65), and the N-methylswietenidine-B (66) were reported from the stem of M. falcatum (Figure 9). The toxicity of all compounds (62-66) was tested in the brine shrimp larvae assay, and their LD₅₀ values were 143, 355.0, 1.39, 2020.0, and 70.5 mg/mL, respectively, indicating that compound (64) was a potent toxic substance.¹⁷

Figure 9

Alkaloids from Micromelum falcatum, M. zeylanicum, and M. integerrimum.

The alkaloids myosmine (67), halfordinol (68), and O-methylhalfordinol (69) were reported from the leaves and young stems of M. zeylanicum.²¹ The methyl carbazole-3-carboxylate (70) was isolated from the leaves of M. integerrimum ³⁸ (Figure 9).

Increased death rates due to lung cancer have necessitated the search for potential novel anticancer compounds such as carbazole derivatives. Carbazoles are aromatic heterocyclic organic compounds, with a tricyclic structure composed of 2 benzene rings each fused onto a 5-membered nitrogen-containing ring with anticancer, antibacterial, and anti-inflammatory activity.

Anti-TB bioassay-directed fractionation led to the isolation of 6 carbazole alkaloids from the CH₂Cl₂ extract of the stem bark of M. hirsutum. The carbazoles including 3-methylcarbazole (71), 3-formylcarbazole (72), lansine (73), 3-formyl-6-methoxycarbazole (74), and methyl carbazole-3-carboxylate (75) were reported from the stem barks of M. hirsutum.¹⁸ A acridone alkaloid, 1,3-dihydroxy-4-methoxy-10-methylacridone (76), was isolated from the leaves of M. integerrimum ³⁸ (Figure 10).

Figure 10

Alkaloids from Micromelum minutum, M. hirsutum, M. zeylanicum, M. glanduliferum, M. falcatum, and M. integerrimum.

Figure 11

Alkaloids from Micromelum falcatum.

Two carbazole alkaloids, 2,7-dihydroxy-3-formyl-1-(30-methyl-20-butenyl)carbazole (77) and 7-methoxy heptaphylline (78), were isolated from the roots of M. glanduliferum by Siridechakorn et al in 1985. They might be a useful chemotaxonomic marker of the species M. glanduliferum and could be used to differentiate M. glanduliferum from other species of Micromelum.²⁰ Micromeline (79) was isolated from the stem barks of M. hirsutum.¹⁸ The alkaloid compounds koenimbine (80), koenine (81), koenigine (82), and koenidine (83) were isolated from the leaves and young stems of M. zeylanicum ²¹ (Figures 10 and 11).

In addition, a carbazole alkaloid, mahanine (84), was isolated from the leaves of M. minutum (Figure 11). It has been shown to exhibit a wide range of pharmacological effects including antimutagenicity against heterocyclic amines, antimicrobial activity against Gram positive bacteria, an anti-inflammatory effect, and it appeared to be cytotoxic against several cancer cell lines.³⁵

Phenethyl cinnamides, micrometam A (85), micrometam D (86), micrometam E (87), and micrometam B (88), and a core of novel marine compound, micrometam C (89), were reported from the whole plant of M. falcatum ^15,39 (Figure 11).

Flavones

A number of phytochemical studies dealing with polymethoxylated flavones from Micromelum spp. have been reported and a large number of flavonol-type metabolites were identified with the occurrence of partially methylated derivatives.¹

Polymethoxylated flavones, 5-hydroxy-3,4ʹ,7,8-tetramethoxyflavone (90), 5,7-dihydroxy-3,4’,8-trimethoxyflavone (91), 5-hydroxy-3,4’,7,8-tetramethoxyflavone (92), and 5-hydroxy-3,4’,6,7,8-pentamethoxyflavone (93), were reported from M. minutum.⁴⁰ Other polymethoxylated flavones such as 3,5,7,4ʹ-tetramethoxyflavone (94), 3,5,7,8,4’-pentamethoxyflavone (95), and 3,5,6,7,4’-pentamethoxyflavone (96) were also reported from the leaves of M. compressum ¹ (Figure 12).

Figure 12

Flavones from Micromelum minutum, M. zeylanicum, and M. compressum.

Three compounds, 5,7-dihydroxy-4’,6,8-trimethoxyflavone (97), 7-hydroxy-4’,5,6,8-tetramethoxyflavone (98), and 7-hydroxy-4’,6,8-trimethoxyflavone-5-ylacetate (99), were isolated from the aerial parts of M. minutum.²⁶ 5-hydroxy-3,3’,4’,7,8-pentamethoxyflavone (100) was also isolated from the leaves and stems of M. zeylanicum ²¹ (Figure 12).

Coumarin and Flavone Condensed Binary Compounds

The compounds 8-((1S,2R)−1-hydroxy-2-(5-hydroxy-6, 8-dimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-7-yloxy)−3-methylbut-3-enyl)−7-methoxy-2H-chromen-2-one (101), 8-((1S,2R) −1-hydroxy-3-methyl-2-(5,6,8-trimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-7-yloxy)but-3-enyl)−7-methoxy-2H-chromen-2-one (102), and 7-((1S,2R)−1-hydroxy-1-(7-methoxy-2-oxo -2H-chromen-8-yl)−3-methylbut-3 -en-2-yloxy)−6,8-dimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-5-yl acetate (103) were reported from the above ground parts of M. mtnutum ²⁶ (Figure 13).

Figure 13

Coumarin and flavone condensed compounds from Micromelum minutum.

Miscellaneous Compounds

The stigmasterol (104) was isolated from the leaves of M. minutum.¹⁰ Two triterpenes, 5(6)-gluten-3α-ol (105) and 5(6)-gluten-3-on (106), were isolated from the leaves’ and barks’ crude petroleum ether and chloroform extracts of M. minutum.¹¹ The derivative of oleic acid with trivial name micromolide (107) was isolated from the stem barks of M. hirsutum ¹⁸ (Figure 14).

Figure 14

Miscellaneous compounds from Micromelum minutum and M. hirsutum.

In 2014, Zhi-yao et al have reported 2 phenylpropanoids, microintegerrin A (108) and microintegerrin B (109), from the air-dried stems and leaves of M. integerrimum. These 2 compounds were tested for their cytotoxicity against 3 cancer cell lines (HeLa, A549, and BGC-823) but did not show any activity.²⁴ Dihydrocinnamic methyl ester derivatives, 3-(5-((2R,3R,4R)−3,4-dihydroxy-4-methyl-5-oxotetrahydrofuran-2-yl)−2-hydroxy-4-methoxyphenyl)propanoic acid (110) and secomicromelin (111), were isolated from the fruits of M. falcatum ⁴ (Figures 7 and 14). Three dihydrocinnamic acid derivatives, 3,4-dihydro-1,2-secomicrominutinin (112), 3,4-dihydro-1,2-secomicrominutinin methylester (113), and 3,4-dihydro-1,2-secomicrominutinin-9-O-glucoside (114), were isolated from the leaves of M. falcatum.¹⁴ Other 3 glucosides of phenylpropanoic acid derivatives, micromelumosides A (115), micromelumosides B (116), and micromelumosides C (117), and sesamin (118) were reported from the aerial parts of M. minutum ⁶ (Figure 7).

Conclusion

Micromelum spp. possess very rich sources of bioactive secondary metabolites. As a member of rutaceae family it contains mainly coumarins (from simple to prenly, and geranyl), alkaloids (quinolidine and carbazole), polymethoxyflavones, and a few glycosides and phenylpropanoic acid derivatives (Table 1). The coumarins are the most abundant compounds from Micromelum spp., and some compounds, such as 8-hydroxyisocapnolactone-2ʹ,3ʹ-diol, have positive effects on the anticancer activity. Currently, at least 118 compounds have been reported from different plant parts of M. integerrimum, M. minutum, M. falcatum, M. compressum, M. glanduliferum, M. hirsutum, and M. zeylanicum (Table 1). Among them, M. integerrimum, M. minutum, and M. falcatum were well studied chemically and pharmacologically and others, M. compressum, M. glanduliferum, M. hirsutum, and M. zeylanicum, have been studied less. So, the review suggests that there is a great potential for researchers to search drug lead secondary metabolites from the genus Micromelum.

Table 1

Isolated Compounds Reported From Micromelum Spp.

No. of compounds	Plant parts	Name of species	References
Simple coumarins
Umbelliferone (1)	Roots	M. minutum	^8,13
7-Hydroxy-6-methoxy-2H-chromen-2-one (2)	Fruits	M. minutum	²³
6-Hydroxy-7-methoxy-2H-chromen-2-one (3)	Leaves and stems	M. integerrimum	²⁴
6-Formyl-7-methoxycoumarin (4)	Leaves and stems	M. zeylanicum	²¹
Osthenon (5)	Roots	M. minutum	⁸
Prenylated coumarins
Osthol (6)	Leaves	M. minutum	⁸
Microfalcrin (7)	Roots	M. falcatum	¹⁶
Micromarin-F (8)	Stems	M. minutum	²⁵
Micromarin-G (9)	Stems	M. minutum	²⁵
Micromarin-H (10)	Stems	M. minutum	²⁵
Murralongin-1 (11)	Fruits	M. minutum	^8,23
Murralongin-2 (12)	Fruits	M. minutum	^8,23
Murralonginol (13)	Fruits	M. minutum	^8,23
Phebalosin (14)	Roots	M. minutum	⁸
Murrangatin (15)	Roots	M. minutum	⁸
Murrangatin acetate (16)	Roots	M. minutum	⁸
Murracarpin (17)	Roots	M. minutum	⁸
Minumicrolin (18)	Roots	M. minutum	⁸
Microminutin (19)	Stem	M. minutum	²⁵
7-Methoxy-8-(4′-methyl-3′-furanyl)coumarin (20)	Fruits	M. falcatum	⁴
Microminutin B (21)	Fruits	M. falcatum	⁴
Microminutin C (22)	Fruits	M. falcatum	⁴
Micromeloside A (23)	Fruits	M. falcatum	⁴
Microcoumaririn (24)	Leaves	M. falcatum	¹⁶
Micromelin (25)	Fruits	M. minutum	²³
Acetyldihydromicromelin A (26)	Aerial parts	M. minutum	²⁶
Hydramicromelin D (27)	Twigs	M. integerrimum	³
Hopeyhopol (28)	Whole plants	M. minutum	²⁸
Marmesin (29)	Whole plants	M. minutum	²⁸
(−) Decursinol (30)	Fruits	M. falcatum	⁴
Micromarin-A (31)	Stems	M. falcatum	^16,22
Micromarin-B (32)	Stems	M. minutum	^16,22
Micromarin-C (33)	Stems	M. minutum	²²
(3S,4S)−3,4-Dihydroxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-ethylenebutyl 3-methylbutanoate (34)	Fruits	M. falcatum	⁴
(3R,4S)−3,4-Dihydroxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-methylenebutyl 3-methylbutanoate (35)	Fruits	M. falcatum	⁴
3-Hydroxy-4-methoxy-4-(7-methoxy-2-oxo-2H-chromen-8-yl)−2-methylenebutyl3-ethylbutanoate (36)	Fruits	M. falcatum	⁴
7-Methoxy-8-(2-hydroxymethyl-1-O-isovaleryl-4-butenyl) coumarin (37)	Stem bark	M. falcatum	²⁹
Murralonginol isovalerate-1 (38)	Stems	M. minutum	²³
Murralonginol isovalerate-2 (39)	Roots	M. minutum	⁸
Minutuminolate (40)	Roots	M. minutum	⁸
7-Demethylmurralonginol isovalerate (41)	Roots	M. minutum	²³
Micromarinate (42)	Fruits	M. falcatum	⁴
8-Hydroxyisocapnolactone-2ʹ,3ʹ-diol (43)	Leaves	M. minutum	^10,11,28,32
8-Methoxycapnolactone (44)	Leaves	M. minutum	^10,11,28,32
3″,4″-Dihydrocapnolactone (45)	Leaves	M. minutum	^10,11,28,32
2ʹ,3ʹ-Epoxyisocapnolactone (46)	Leaves	M. minutum	^10,11,28,32
8-Hydroxy-3″,4″-dihydrocapno lactone-2ʹ,3ʹ-diol (47)	Leaves	M. minutum	^10,11,32
8,4-Dihydroxy-3,4-dihydro capnolactone-2,3-diol (48)	Leaves	M. minutum	¹⁰ ^, ^11,32
Minutin A (49)	Leaves	M. minutum	¹⁰ ^, ^11,32
Minutin B (50)	Leaves	M. minutum	¹⁰ ^, ^11,32
Micromelosidester (51)	Leaves	M. falcatum	⁴
Microminutinin (52)	Leaves	M. falcatum	⁴
6-Methoxymicrominutinin (53)	Leaves	M. falcatum	^16,25
Integerrimelin (54)	Twigs	M. integerrimum	³
(1R,3R,4R,6S)−4-(7-Methoxy-2-oxo-2H-chromen-6-yl)−1-methyl-3,6-dioxabicyclo[3.1.0]hexan-2-yl acetate (55)	Leaves	M. integerrimum	³³
scopolin (56)	Stems and leaves	M. integerrimum	²⁴
7-Methoxy-8-(1-hydroxy-2-O-β-glucopyranosyl-3-Methyl-4-butene-1-yl) coumarin (57)	Stem bark	M. falcatum	²⁹
Micromelumoside D (58)	Aerial parts	M. minutum	⁶
Hydramicromelinin (59)	Bark	M. minutum	³⁴
Micromelinin (60)	Bark	M. minutum	³⁴
1-O-β-D-Glucopyranosylmarmesin (61)	Bark	M. minutum	³⁴
Alkaloids
2-(3-Hydroxy-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (62)	Stems	M. falcatum	¹⁷
3-Hydroxy-1-methyl-3-(2-oxopropyl)quinoline-2,4(1H,3H)-dione (63)	Stems	M. falcatum	¹⁷
N-Methylflindersine (64)	Stems	M. falcatum	¹⁷
4-Hydroxy-3-methoxy-1-methyl-2(1 H)-quinolinone (65)	Stems	M. falcatum	¹⁷
N-Methylswietenidine-B (66)	Stems	M. falcatum	¹⁷
Myosmine (67)	Leaves and stem	M. zeylanicum	²¹
Halfordinol (68)	Leaves and stem	M. zeylanicum	²¹
O-Methylhalfordinol (69)	Leaves and stem	M. zeylanicum	²¹
Methyl carbazole-3-carboxylate (70)	Leaves	M. integerrimum	³⁸
3-Methylcarbazole (71)	Stem barks	M. hirsutum	¹⁸
3-Formylcarbazole (72)	Stem barks	M. hirsutum	¹⁸
Lansine (73)	Stem barks	M. hirsutum	¹⁸
3-Formyl-6-methoxycarbazole (74)	Stem barks	M. hirsutum	¹⁸
Methyl carbazole-3-carboxylate (75)	Leaves	M. integerrimum	³⁸
1,3-Dihydroxy-4-methoxy-10-methylacridone (76)	Stem bark	M. hirsutum	¹⁸
2,7-Dihydroxy-3-formyl-1-(30-methyl-20-butenyl)carbazole (77)	Roots	M. glanduliferlum	²⁰
7-Methoxy heptaphylline (78)	Roots	M. glanduliferlum	²⁰
Micromeline (79)	Stem bark	M. hirsutum	¹⁸
Koenimbine (80)	Leaves and stem	M. zeylanicum	²¹
Koenine (81)	Leaves and stem	M. zeylanicum	²¹
Koenigine (82)	Leaves and stem	M. zeylanicum	²¹
Koenidine (83)	Leaves and stem	M. zeylanicum	²¹
Mahanine (84)	Roots	M. minutum	³⁵
Miscellaneous compounds
Micrometam A (85)	Whole plants	M. falcatum	¹⁵
Micrometam D (86)	Whole plants	M. falcatum	¹⁵
Micrometam E (87)	Whole plants	M. falcatum	¹⁵
Micrometam B (88)	Whole plants	M. falcatum	¹⁵
Micrometam C (89)	Whole plants	M. falcatum	¹⁵
Polymethoxylated flavones
5-Hydroxy-3,4ʹ,7,8-tetramethoxyflavone (90)	Aerial parts	M. minutum	⁴⁰
5,7-Dihydroxy-3,4’,8-trimethoxyflavone (91)	Aerial parts	M. minutum	⁴⁰
5-Hydroxy-3,4’,7,8-tetramethoxyflavone (92)	Aerial parts	M. minutum	⁴⁰
5-Hydroxy-3,4’,6,7,8-pentamethoxyflavone (93)	Leaves	M. minutum	⁴⁰
3,5,7,4ʹ-Tetramethoxyflavone (94)	Leaves	M. compressum	¹
3,5,7,8,4’-Pentamethoxyflavone (95)	Leaves	M. compressum	¹
3,5,6,7,4’-Pentamethoxyflavone (96)	Leaves	M. compressum	¹
5,7-Dihydroxy-4’,6,8-trimethoxyflavone (97)	Aerial parts	M. minutum	²⁶
7-Hydroxy-4’,5,6,8-tetramethoxyflavone (98)	Aerial parts	M. minutum	²⁶
7-Hydroxy-4’,6,8-trimethoxyflavone −5-ylacetate (99)	Aerial parts	M. minutum	²⁶
5-Hydroxy-3,3’,4’,7,8-pentamethoxyflavone (100)	Leaves and stems	M. zeylanicum	²¹
Coumarin and flavone condensed compounds
8-((1S,2R)−1-Hydroxy-2-(5-hydroxy-6,8-dimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-7-yloxy)−3-methylbut-3-enyl)−7-methoxy-2H-chromen-2-one (101)	Aerial parts	M. minutum	²⁶
8-((1S,2R)−1-Hydroxy-3-methyl-2-(5,6,8-trimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-7-yloxy)but-3-enyl)−7-methoxy-2H-chromen-2-one (102)	Aerial parts	M. minutum	²⁶
7-((1S,2R)−1-Hydroxy-1-(7-methoxy-2-oxo-2H-chromen-8-yl)−3-methylbut-3-en-2-yloxy)−6,8-dimethoxy-2-(4-methoxyphenyl)−4-oxo-4H-chromen-5-yl acetate (103)	Aerial parts	M. minutum	²⁶
Stigmasterol and triterpenes
Stigmasterol (104)	Leaves	M. minutum	¹⁰
5(6)-Gluten-3α-ol (105)	Leaves and barks	M. minutum	²³
5(6)-Gluten-3-one (106)	Leaves and barks	M. minutum	²³
Derivative of oleic acid and phenylpropanoic acid
Micromolide (107)	Stem barks	M. hirsutum	¹⁸
Microintegerrin A (108)	stems and leaves	M. integerrimum	²⁴
Microintegerrin B (109)	stems and leaves	M. integerrimum	²⁴
3-(5-((2R,3R,4R)−3,4-Dihydroxy-4-methyl-5-oxotetrahydrofuran-2-yl)−2-hydroxy-4-methoxyphenyl)propanoic acid (110)	fruits	M. falcatum	⁴
Secomicromelin (111)	fruits	M. falcatum	⁴
3,4-Dihydro-1,2-secomicrominutinin (112)	leaves	M. falcatum	¹⁴
3,4-Dihydro-1,2-secomicrominutinin methylester (113)	leaves	M. falcatum	¹⁴
3,4-Dihydro-1,2-secomicrominutinin-9-O-glucoside (114)	leaves	M. falcatum	¹⁴
Micromelumosides A (115)	aerial parts	M. minutum	⁶
Micromelumosides B (116)	aerial parts	M. minutum	⁶
Micromelumosides C (117)	aerial parts	M. minutum	⁶
Sesamin (118)	bark	M. minutum	³⁴

Footnotes

Acknowledgments

Appreciation is conveyed to Prof M. Iqbal Choudhary from H.E.J. Research Institute of Chemistry, International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan, for his help in improving this review article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Nanik Siti Aminah

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Phytoconstituents of Genus Micromelum and Their Bioactivity—a Review

Abstract

Keywords

Introduction to Chemical Constituents of Genus Mocromelum and Their Bioactivity

Phytochemical Aspects of Micromelum Spp. and Their Tested Bioactivities

Coumarins

Alkaloids

Flavones

Coumarin and Flavone Condensed Binary Compounds

Miscellaneous Compounds

Conclusion

Footnotes

Acknowledgments

Declaration of Conflicting Interests

Funding

ORCID iD

References