# Chemical Constituents and Biological Activities ofFicus tikoua Bureau

Authors: Liangliang Yao; Shengchao Zhao; Wei Liu; Guanzhen Wang; Chunpeng (Craig) Wan
Journal: Journal of Chemistry
 (2022)

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## Abstract

Ficus tikoua Bureau (F. tikoua Bur.) is a perennial woody vine in the Moraceae family that has been used as a traditional folk medicine for centuries to treat many diseases such as chronic bronchitis, diarrhea, dysentery, rheumatism, and other inflammation-related diseases in certain parts of China, India, Vietnam, and Laos. This medicinal plant contains beneficial secondary metabolites belonging to various chemical classes, including flavonoids, phenolics, terpenoids, steroids, coumarins, and alkaloids. In this review, we have summarized the natural compounds isolated from F. tikoua Bur. and their biological effects.


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## Body

## 1. Introduction

The growing scourge of communicable and noncommunicable diseases (cancer, diabetes, cardiovascular disease, and chronic lung disease) and the need to find suitable drugs against them are a great challenge to scientists and the society. Similarly, the rising instances of antibiotic-resistant superbugs have made some existing antibiotics ineffective and obsolete. A large population worldwide is afflicted with these diseases, which is causing a great loss of human lives and burden on the economy. Tackling this problem demands science to be one step ahead by researching new drug molecules against such diseases. In this endeavor, plants with their rich diversity of natural compounds have emerged as an option for developing new and promising therapeutic agents and drugs that can act against diseases, with little or no side effects.Despite the current popularity of synthetic chemistry for the drug development, the application of plants for treating and preventing diseases is in no way less significant [1]; for example, 11% of all the drugs that come under the World Health Organization’s essential category is of plant origin [1]. The importance of natural resources in drug development can be understood by the fact that, over a period of 40 years from 1981 to 2020, up to 50% of the approved drugs come from natural products including plants [2]. Plants have been used since time immemorial for their properties. Many plant-derived medicines have been utilized in the treatment of multiple diseases. Plant-derived compounds have shown encouraging results in surmounting antibiotic resistance in pathogenic bacteria [3]. Further, a report studied 122 plant-derived drugs and found that, out of these drugs, 80% had already related to their original ethnomedical and ethnopharmacological purpose, thus emphasizing the importance of traditional folk medicinal plants in the modern medicine [4]. Plant products are also increasingly being used in the cosmetic industry as an ecofriendly alternative to the synthetic ingredients [5–7]. Ficus tikoua Bureau (F. tikoua Bur.) is one such ethnomedicinal plant that is commonly found in China, India, Vietnam, and Laos [8]. It is used as a medicinal and edible plant by ethnic groups such as Guan et al. and Sun et al. [9, 10] in China. It is a perennial woody vine of Ficus genus in the Moraceae family. The whole plant of F. tikoua Bur. is used as a traditional folk medicine to treat sore throat, cough, diarrhea, jaundice, rheumatism, edema, and dyspepsia [11–13]. In recent years, F. tikoua Bur. is gaining more and more attention as studies have shown that its extract has hypoglycemic [9], antibacterial [14], and antioxidant potential [14–16].As research into plant-derived phytochemicals is increasing, regional medicinal plants from developing countries must also be promoted for the conservation of ecology and traditional medicinal knowledge and for providing medicine at low cost. With this background, herein, we have organized and summarized chemically diverse natural compounds isolated fromF. tikoua Bur. and main experimental findings on their biological effects. This review will be helpful in underlining the emerging importance of the ethnomedicinal plant F. tikoua Bur. in medicine and the chemistry of plant-derived natural compounds.


## 2. Chemical Constituents

F. tikoua Bur. is rich in many secondary metabolites belonging to different phytochemical classes, including flavonoids, phenolic acids, terpenoids, steroids, coumarins, chromones, alkaloids, and hydrocarbons.


### 2.1. Flavonoids and Lignans

Approximately 57 flavonoid and lignan compounds (Figure1; Table 1) including 21 isoflavones, 10 flavanones, 7 flavones, 7 flavanonols, 4 flavanols, 4 proanthocyanidins, 3 flavonol glycosides, and 1 isoflavanones have been identified from F. tikoua Bur. to date. Zhou et al. [17] in 2022 reported the isolation of twenty-two flavonoids including flavanones, isoflavones, and flavones from the petroleum ether and ethyl acetate portions of the 95% ethanol extract of F. tikoua Bur. aerial parts. Fu et al. [16] isolated a new isoflavonoid, ficusin C, from the rhizomes of F. tikoua Bur. Wei et al. [18] obtained seven flavonoid compounds (genistein, myrsininone A, wighteone or erythrinin B, lupiwighteone, naringenin, 6-prenylnaringenin, and 8-prenylnaringenin) from the F. tikoua Bur. stem for the first time. There are only few reports of extraction of flavanols and flavonols from F. tikoua Bur. Wei’s group [19] isolated catechin and quercetin-catechin dimer from the water-soluble portion of the methanol extract of F. tikoua Bur. stems. In the same paper, the authors also isolated three proanthocyanidins: arecatannin, procyanidin B, and (epi)afzelechin-(epi)catechin. Yang’s group [20] and Fu’s group [16] reported the isolation of flavonol quercetin from F. tikoua Bur. Zhou et al. [21] in 2018 reported the isolation of a new isoflavone (ficustikounone A) and 22 other flavonoids (flavone, flavanone, isoprenylated flavanone, and isoflavones) from F. tikoua Bur. He et al. [22] used aerial parts of F. tikoua Bur. to extract lignans and neolignans, such as ssioriside and (+)-isolariciresinol, (−)-isolariciresinol-9-O-β-D-glucopyranoside. Yang’s group [23] investigated the flavonoid content in different parts of F. tikoua Bur.: old leaves, young leaves, and stems. The authors found the highest content of flavonoids in the old leaves of the plant (147.5 mg/g), whereas the flavonoid contents in young leaves and stems of the plant were 107.67 mg/g and 91.69 mg/g, respectively.Figure 1
Structures of the flavonoids and lignans found inF. tikoua Bur.
(a)(b)Table 1
Flavonoids and lignans isolated fromF. tikoua Bur.
No.Compound namesFlavonoid classReferences1ApigeninFlavone[14, 20, 26]2QuercetinFlavonol[14, 16]3LuteolinFlavone[14]4NicotiflorinFlavonol glycoside[19]5RutinFlavonol glycoside[19]67-O-methylapigeninFlavone[21]7KaempferolFlavonol[17]8AstragalinFlavone[17]9IsovitexinFlavone[17]10Quercetin-3-O-β-D-glucopyranosideFlavonol glycoside[17]11(2R, 3R)-(+)-dihydroquercetinFlavanonol[14]12AromadendrinFlavanonol[17]13EriodictyolFlavanone[14, 17, 18]14NaringeninFlavanonol[14, 17]158-PrenylnaringeninFlavanone[18, 20]16NeophellamuretinFlavanonol[21]176-prenylnaringeninFlavanone[18]18(S)-5,7,3,4-tetrahydroxy-2-(3-methylbut-2-enyl)flavanoneFlavanone[32]19Ficustikousins AFlavanone[32]20Ficustikousins BFlavanone[21, 32]21(S)-paratocarpin KFlavanone[32]22Afzelin AFlavanonol[17]23(1″R)-5,4′,1″-trihydroxy-6,7-(3″,3″-dimethylchroman) flavoneFlavone[21]24CarpachromeneFlavone[17, 21]25CitflavanoneFlavanone[17, 21]26YukovanolFlavanonol[17]27CitrusinolFlavonol[17]28Phellodensin AFlavanonol[17]29AF-6PN-3Flavanone[21]30Phellodensin DFlavanone[21]31Erythrinin CIsoflavone[21]32Ficustikounone AIsoflavanone[21]33Myrsininone AIsoflavone[18, 21]34GenisteinIsoflavone[18, 21, 26]353′-(3-Methylbut-2-enyl)biochanin AIsoflavone[21, 32]36WighteoneIsoflavone[17, 18, 21, 37]37LupiwighteoneIsoflavone[18, 37]38IsowigtheoneIsoflavone[21]39Vogelin EIsoflavone[21]40Schliebenone AIsoflavone[21]41PrunetinIsoflavone[17]42Genistein-4-O-β-D-glucopyranosideIsoflavone[17]43Ficusin CIsoflavone[16]446-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavoneIsoflavone[17]455,3′,4′-trihydroxy-2″,2″-dimethylpyrano (5″, 6″ : 7, 8) isoflavoneIsoflavone[18]46DerroneIsoflavone[17]47HydroxyderroneIsoflavone[21]48Genistein 7-O-β-D-glucopyranosideIsoflavone[17]49CatechinFlavonol[19, 22]50Ficusin AIsoflavone[16, 17]51AlpinumisoflavoneIsoflavone[16, 17]524′-O-methyl-alpinumisoflavoneIsoflavone[16]53HydroxyalpinumisoflavoneIsoflavone[27]54ArecatanninProanthocyanidin[19]55Quercetin-catechinProanthocyanidin[19]56(epi)afzelechin-(epi)catechinProanthocyanidin[19]57Procyanidin BProanthocyanidin[19]


### 2.2. Phenolic Acids and Phenolic Glycosides

Phenolic acids and their derivatives (esters, aldehydes, and glycosides) have also been reported in the extract ofF. tikoua Bur. (Figure 2; Table 2). Jiang et al. [24] isolated ten phenolic glycosides from the ethanol extract of F. tikoua; among these ten phenolic glycosides, four were isolated for the first time (Table 2). The other examples of phenolic acids and their derivatives isolated from F. tikoua Bur. are as follows: caffeic acid methyl ester [9], o-hydroxybenzoic acid or salicylic acid [25], 3,4-dihydroxybenzoic acid or protocatechuic acid [25, 26], p-hydroxybenzoic acid [26], vanillic acid [27], 3,4-dihydroxybenzaldehyde [26], and protocatechuic acid methyl ester [26].Figure 2
Structures of the phenolic acids and their derivatives found inF. tikoua Bur.Table 2
Phenolic glycosides isolated fromF. tikoua Bur.
No.Compound namesReference58Salicylic acid[25]59Protocatechuic acid methyl ester[26]60p-Hydroxybenzoic acid[26]61Vanillic acid[24]623,4-Dihydroxybenzaldehyde[26]63Methyl p-coumarate[9]64Caffeic acid methyl ester[9]652-Methoxy-4-allylphenyl-1-O-β-D-apiofuranosyl-(1⟶6)-β-D-glucopyranoside[24]662-Ethylene-3,5,6-trimethyl-4-phenol-1-O-β-D-xylopyranosyl-(1⟶6)-β-D-glucopyranoside[24]673-Methoxy-4-O-β-D-apiofuranosyl-(1⟶2)-β-D-glucopyranosylpropiophenone[24]683-Hydroxy-1-(4-O-β-D-glucopyranosyl-3-methoxyphenyl) propan-1-one[24]693-Methoxy-4-O-β-D-apiofurano-syl-(1⟶6)-β-D-glucopyranosylpropiophenone[24]70Baihuaqianhuoside[24]714-Hydroxy-3,5-bis(30-methyl-2-butenyl)benzoic acid-O-β-D-glucopyranoside[24]723,4,5-Trimethoxyphenol-1-O-β-D-apiofuranosyl-(1⟶6)-β-D-glucopyranoside[24]733,4,5-Trimethoxyphenol-1-O-β-D-glucopyranoside[24]743,5-Dimethoxy-4-hydroxybenzoicacid-O-β-D-glucopyranoside[24]


### 2.3. Terpenes or Terpenoids

Phytochemical investigation onF. tikoua Bur. by many research groups has also yielded terpene compounds (Figure 3; Table 3) [20, 24, 27]. Terpenes are also called isoprenoids because they contain five-carbon isoprene units or molecules (CH2=C(CH3)CH=CH2) as a building block in their structures. On the basis of the number of isoprene units, terpenes can be classified into following groups: (i) monoterpenes (2 isoprene units), (ii) sesquiterpenes (3 isoprene units), (iii) diterpenes (4 isoprene units), (iv) triterpenes (6 isoprene units), and (v) tetraterpenes (8 isoprene units). Terpenes of all classes except tetraterpenes have been isolated from F. tikoua Bur.Figure 3
Structures of the terpenes and terpenoids found inF. tikoua Bur.Table 3
Terpenes isolated fromF. tikoua Bur.
No.Terpene compoundsTerpene classReference75α-PineneMonoterpene[28]76β-PineneMonoterpene[28]77CampheneMonoterpene[28]781,8-CineoleMonoterpene[28]79β-DamascenoneMonoterpene[28]801-Bornyl acetateMonoterpene[28]81α-TerpineolMonoterpene[28]82LinaloolMonoterpene[28]83ThymolMonoterpene[28]84Bluemenol ASesquiterpene[28]85β-CaryophylleneSesquiterpene[28]86Caryophyllene oxideSesquiterpene[28]87δ-CadineneSesquiterpene[28]88β-SelineneSesquiterpene[28]89TotarolDiterpene[28]903,4a,7,7,10a-pentamethyl-3-vinyl-dodecahydro-1H-benzo[f]chromeneDiterpene[34]91Farnesyl acetoneDiterpene[28]924,8,12,16-Tetramethylheptadecan-4-olideDiterpene[28]93β-SitosterolTriterpene[14, 26, 27, 29]94Oleanolic acidTriterpene[9, 14, 29]953-O-acetyloleanolic acidTriterpene[14]96β-AmyrenoneTriterpene[30]97β-Amyrin acetateTriterpene[30]98Germanicol acetateTriterpene[30]9922-Oxo-20-taraxasten-3β-olTriterpene[26]100α-Amyrin acetateTriterpene[25, 30]101α-MyrenoneTriterpene[25, 30]102β-Amyrin palmitateTriterpene[30]103Ursolic acidTriterpene[30]104α-AmyrinTriterpene[29]Very recently, Tian et al. [28] identified many terpene compounds in the essential oil of F. tikoua Bur. Sesquiterpenes containing different skeletons such as eudesmane (e.g., β-selinene), cadinane (e.g., α-cadinol), cedrane (e.g., α-cedrol), farnesane (e.g., d-nerolidol), and aromadendrane (e.g., spathulenol) have been identified in F. tikoua Bur.


### 2.4. Steroids

Steroids are another important class of chemical compounds that have been isolated fromF. tikoua Bur. (Figure 4; Table 4). These include 5α-stigmastane-3,6-dione, β-sitosterol, ergosterol, stigmastane-3β,5α,6β-triol, stigmasta-3,5-dien-7-one, stigmast-4-en-3-one, β-stigmasterol, simiarenol, and 3β-hydroxystigmast-5-en-7-one [9, 20, 26, 29–31]. Guan’s group [9] have also reported the isolation of a steroidal glycoside named daucosterol from F. tikoua Bur,Figure 4
Structures of the steroids found inF. tikoua Bur.Table 4
Steroids isolated fromF. tikoua Bur.
No.Compound namesReference1053β-Hydroxystigmast-5-en-7-one[20]106β-Sitosterol[9, 20, 27]107Daucosterol[9]1085α-Stigmastane-3,6-dione[20]109Stigmastane-3β,5α,6β-triol[30]110Stigmasta-3,5-dien-7-one[31]111Stigmast-4-en-3-one[9, 31]112Ergosterol[31]113β-Stigmasterol[20, 27]


### 2.5. Other Compounds

Chemical compounds belonging to chemical classes other than previously mentioned have also been reported fromF. tikoua Bur. by multiple studies (Figure 5; Table 5). Wei et al. [15] isolated two benzofuran glycosides, 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside and 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-D-glucopyranoside, from the extract of F. tikoua Bur. stems. Similarly, another benzofuran glycoside, 6-(2-carboxyvinyl)-7-methoxy-5-hydroxy-benzofuran-5-O-β-D-glucopyranoside, was obtained by Wei et al. [19] from the water-soluble portion of the methanol extract of F. tikoua Bur. stems.Figure 5
Structures of some of other compounds found inF. tikoua Bur.Table 5
Other compounds found inF. tikoua Bur.
No.Compound namesReference1146-Carboxyethyl-5-hydroxybenzofuran[15]1155-O-β-D-glucopyranoside, 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside[15]1166-(2-Carboxyvinyl)-7-methoxy-5-hydroxy-benzofuran[19]1175-O-β-D-glucopyranoside (±)-ficunomone[17]118Angelicin[31]119Isobergapten[31]120Esculetin[26]121Indole-3-carboxylic acid[26]122Bergapten[9, 22, 29, 30, 32]1235,7-Dihydroxychromone[26]124Noreugenin[26]125Alloptaeroxylin[26]126Dimethyl phthalate[31]127Dibutyl phthalate[31]128Diisobutyl phthalate[31]129Dihexyl phthalate[31]130Marmesin[31]131Triethyl citrate[31]1322,6-Dimethoxy-1,4-benzoquinone[27]133Allantoin[9]134Neoechinulin A[26]Coumarins and chromones are oxygenated heterocyclic compounds that belong to the benzopyrone chemical class. Bergapten is the most common coumarin that has been isolated fromF. tikoua Bur. by more than one study [9, 22, 29, 30, 32]. Esculetin isolated by Zhou et al. [26] and nodakenin and psoralen isolated by He et al. [22] are other examples of coumarins presented in F. tikoua. Very recently, Zhou’s group [17, 26] reported isolation of one new and three chromone compounds from the aerial parts of F. tikoua: (±)-ficunomone, 5,7-dihydroxychromone, noreugenin, and alloptaeroxylin. They also reported the extraction of two alkaloids, neoechinulin A and indole-3-carboxylic acid, for the first time from F. tikoua Bur.Yang’s group [33] in 2016 investigated the F. tikoua Bur. fruit for the identification of volatile compounds. The authors detected the presence of 152 chemical compounds in F. tikoua Bur. fruits. Among these, esters, alcohols, and alkenes were prominent aroma components class accounting for 33.06%, 13.14%, and 13.18%, respectively, of the total aroma component detected in the F. tikoua Bur. fruits. The major aroma compounds found in the study were as follows: guaiacol, cyclobutane carboxylic acid dodecyl ester, n-tridecane, 2-tridecanone, cyclohexasiloxane, cyclobutanecarboxylic acid decyl ester, methyl nonyl ketone, and acetic acid.Many fatty acids (saturated and unsaturated both), fatty acid methyl esters, fatty acid ethyl esters, fatty acid butyl esters, fatty acid isopropyl esters, and fatty aldehydes have been reported fromF. tikoua Bur. extracts [28, 34]. Additionally, benzoquinone [27], imidazole [9], alpha-tocopherol [34], naphthalene [22], and numerous hydrocarbons (alkanes, alkenes, and styrene) have also been identified in F. tikoua Bur. Tian’s group [28] identified fifty-three compounds in the essential oil of F. tikoua Bur. by GC-FID/MS, and among the identified components, palmitic acid (51.13%) and linoleic acid (47.54%) were the major fraction.


## 2.1. Flavonoids and Lignans

Approximately 57 flavonoid and lignan compounds (Figure1; Table 1) including 21 isoflavones, 10 flavanones, 7 flavones, 7 flavanonols, 4 flavanols, 4 proanthocyanidins, 3 flavonol glycosides, and 1 isoflavanones have been identified from F. tikoua Bur. to date. Zhou et al. [17] in 2022 reported the isolation of twenty-two flavonoids including flavanones, isoflavones, and flavones from the petroleum ether and ethyl acetate portions of the 95% ethanol extract of F. tikoua Bur. aerial parts. Fu et al. [16] isolated a new isoflavonoid, ficusin C, from the rhizomes of F. tikoua Bur. Wei et al. [18] obtained seven flavonoid compounds (genistein, myrsininone A, wighteone or erythrinin B, lupiwighteone, naringenin, 6-prenylnaringenin, and 8-prenylnaringenin) from the F. tikoua Bur. stem for the first time. There are only few reports of extraction of flavanols and flavonols from F. tikoua Bur. Wei’s group [19] isolated catechin and quercetin-catechin dimer from the water-soluble portion of the methanol extract of F. tikoua Bur. stems. In the same paper, the authors also isolated three proanthocyanidins: arecatannin, procyanidin B, and (epi)afzelechin-(epi)catechin. Yang’s group [20] and Fu’s group [16] reported the isolation of flavonol quercetin from F. tikoua Bur. Zhou et al. [21] in 2018 reported the isolation of a new isoflavone (ficustikounone A) and 22 other flavonoids (flavone, flavanone, isoprenylated flavanone, and isoflavones) from F. tikoua Bur. He et al. [22] used aerial parts of F. tikoua Bur. to extract lignans and neolignans, such as ssioriside and (+)-isolariciresinol, (−)-isolariciresinol-9-O-β-D-glucopyranoside. Yang’s group [23] investigated the flavonoid content in different parts of F. tikoua Bur.: old leaves, young leaves, and stems. The authors found the highest content of flavonoids in the old leaves of the plant (147.5 mg/g), whereas the flavonoid contents in young leaves and stems of the plant were 107.67 mg/g and 91.69 mg/g, respectively.Figure 1
Structures of the flavonoids and lignans found inF. tikoua Bur.
(a)(b)Table 1
Flavonoids and lignans isolated fromF. tikoua Bur.
No.Compound namesFlavonoid classReferences1ApigeninFlavone[14, 20, 26]2QuercetinFlavonol[14, 16]3LuteolinFlavone[14]4NicotiflorinFlavonol glycoside[19]5RutinFlavonol glycoside[19]67-O-methylapigeninFlavone[21]7KaempferolFlavonol[17]8AstragalinFlavone[17]9IsovitexinFlavone[17]10Quercetin-3-O-β-D-glucopyranosideFlavonol glycoside[17]11(2R, 3R)-(+)-dihydroquercetinFlavanonol[14]12AromadendrinFlavanonol[17]13EriodictyolFlavanone[14, 17, 18]14NaringeninFlavanonol[14, 17]158-PrenylnaringeninFlavanone[18, 20]16NeophellamuretinFlavanonol[21]176-prenylnaringeninFlavanone[18]18(S)-5,7,3,4-tetrahydroxy-2-(3-methylbut-2-enyl)flavanoneFlavanone[32]19Ficustikousins AFlavanone[32]20Ficustikousins BFlavanone[21, 32]21(S)-paratocarpin KFlavanone[32]22Afzelin AFlavanonol[17]23(1″R)-5,4′,1″-trihydroxy-6,7-(3″,3″-dimethylchroman) flavoneFlavone[21]24CarpachromeneFlavone[17, 21]25CitflavanoneFlavanone[17, 21]26YukovanolFlavanonol[17]27CitrusinolFlavonol[17]28Phellodensin AFlavanonol[17]29AF-6PN-3Flavanone[21]30Phellodensin DFlavanone[21]31Erythrinin CIsoflavone[21]32Ficustikounone AIsoflavanone[21]33Myrsininone AIsoflavone[18, 21]34GenisteinIsoflavone[18, 21, 26]353′-(3-Methylbut-2-enyl)biochanin AIsoflavone[21, 32]36WighteoneIsoflavone[17, 18, 21, 37]37LupiwighteoneIsoflavone[18, 37]38IsowigtheoneIsoflavone[21]39Vogelin EIsoflavone[21]40Schliebenone AIsoflavone[21]41PrunetinIsoflavone[17]42Genistein-4-O-β-D-glucopyranosideIsoflavone[17]43Ficusin CIsoflavone[16]446-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavoneIsoflavone[17]455,3′,4′-trihydroxy-2″,2″-dimethylpyrano (5″, 6″ : 7, 8) isoflavoneIsoflavone[18]46DerroneIsoflavone[17]47HydroxyderroneIsoflavone[21]48Genistein 7-O-β-D-glucopyranosideIsoflavone[17]49CatechinFlavonol[19, 22]50Ficusin AIsoflavone[16, 17]51AlpinumisoflavoneIsoflavone[16, 17]524′-O-methyl-alpinumisoflavoneIsoflavone[16]53HydroxyalpinumisoflavoneIsoflavone[27]54ArecatanninProanthocyanidin[19]55Quercetin-catechinProanthocyanidin[19]56(epi)afzelechin-(epi)catechinProanthocyanidin[19]57Procyanidin BProanthocyanidin[19]


## 2.2. Phenolic Acids and Phenolic Glycosides

Phenolic acids and their derivatives (esters, aldehydes, and glycosides) have also been reported in the extract ofF. tikoua Bur. (Figure 2; Table 2). Jiang et al. [24] isolated ten phenolic glycosides from the ethanol extract of F. tikoua; among these ten phenolic glycosides, four were isolated for the first time (Table 2). The other examples of phenolic acids and their derivatives isolated from F. tikoua Bur. are as follows: caffeic acid methyl ester [9], o-hydroxybenzoic acid or salicylic acid [25], 3,4-dihydroxybenzoic acid or protocatechuic acid [25, 26], p-hydroxybenzoic acid [26], vanillic acid [27], 3,4-dihydroxybenzaldehyde [26], and protocatechuic acid methyl ester [26].Figure 2
Structures of the phenolic acids and their derivatives found inF. tikoua Bur.Table 2
Phenolic glycosides isolated fromF. tikoua Bur.
No.Compound namesReference58Salicylic acid[25]59Protocatechuic acid methyl ester[26]60p-Hydroxybenzoic acid[26]61Vanillic acid[24]623,4-Dihydroxybenzaldehyde[26]63Methyl p-coumarate[9]64Caffeic acid methyl ester[9]652-Methoxy-4-allylphenyl-1-O-β-D-apiofuranosyl-(1⟶6)-β-D-glucopyranoside[24]662-Ethylene-3,5,6-trimethyl-4-phenol-1-O-β-D-xylopyranosyl-(1⟶6)-β-D-glucopyranoside[24]673-Methoxy-4-O-β-D-apiofuranosyl-(1⟶2)-β-D-glucopyranosylpropiophenone[24]683-Hydroxy-1-(4-O-β-D-glucopyranosyl-3-methoxyphenyl) propan-1-one[24]693-Methoxy-4-O-β-D-apiofurano-syl-(1⟶6)-β-D-glucopyranosylpropiophenone[24]70Baihuaqianhuoside[24]714-Hydroxy-3,5-bis(30-methyl-2-butenyl)benzoic acid-O-β-D-glucopyranoside[24]723,4,5-Trimethoxyphenol-1-O-β-D-apiofuranosyl-(1⟶6)-β-D-glucopyranoside[24]733,4,5-Trimethoxyphenol-1-O-β-D-glucopyranoside[24]743,5-Dimethoxy-4-hydroxybenzoicacid-O-β-D-glucopyranoside[24]


## 2.3. Terpenes or Terpenoids

Phytochemical investigation onF. tikoua Bur. by many research groups has also yielded terpene compounds (Figure 3; Table 3) [20, 24, 27]. Terpenes are also called isoprenoids because they contain five-carbon isoprene units or molecules (CH2=C(CH3)CH=CH2) as a building block in their structures. On the basis of the number of isoprene units, terpenes can be classified into following groups: (i) monoterpenes (2 isoprene units), (ii) sesquiterpenes (3 isoprene units), (iii) diterpenes (4 isoprene units), (iv) triterpenes (6 isoprene units), and (v) tetraterpenes (8 isoprene units). Terpenes of all classes except tetraterpenes have been isolated from F. tikoua Bur.Figure 3
Structures of the terpenes and terpenoids found inF. tikoua Bur.Table 3
Terpenes isolated fromF. tikoua Bur.
No.Terpene compoundsTerpene classReference75α-PineneMonoterpene[28]76β-PineneMonoterpene[28]77CampheneMonoterpene[28]781,8-CineoleMonoterpene[28]79β-DamascenoneMonoterpene[28]801-Bornyl acetateMonoterpene[28]81α-TerpineolMonoterpene[28]82LinaloolMonoterpene[28]83ThymolMonoterpene[28]84Bluemenol ASesquiterpene[28]85β-CaryophylleneSesquiterpene[28]86Caryophyllene oxideSesquiterpene[28]87δ-CadineneSesquiterpene[28]88β-SelineneSesquiterpene[28]89TotarolDiterpene[28]903,4a,7,7,10a-pentamethyl-3-vinyl-dodecahydro-1H-benzo[f]chromeneDiterpene[34]91Farnesyl acetoneDiterpene[28]924,8,12,16-Tetramethylheptadecan-4-olideDiterpene[28]93β-SitosterolTriterpene[14, 26, 27, 29]94Oleanolic acidTriterpene[9, 14, 29]953-O-acetyloleanolic acidTriterpene[14]96β-AmyrenoneTriterpene[30]97β-Amyrin acetateTriterpene[30]98Germanicol acetateTriterpene[30]9922-Oxo-20-taraxasten-3β-olTriterpene[26]100α-Amyrin acetateTriterpene[25, 30]101α-MyrenoneTriterpene[25, 30]102β-Amyrin palmitateTriterpene[30]103Ursolic acidTriterpene[30]104α-AmyrinTriterpene[29]Very recently, Tian et al. [28] identified many terpene compounds in the essential oil of F. tikoua Bur. Sesquiterpenes containing different skeletons such as eudesmane (e.g., β-selinene), cadinane (e.g., α-cadinol), cedrane (e.g., α-cedrol), farnesane (e.g., d-nerolidol), and aromadendrane (e.g., spathulenol) have been identified in F. tikoua Bur.


## 2.4. Steroids

Steroids are another important class of chemical compounds that have been isolated fromF. tikoua Bur. (Figure 4; Table 4). These include 5α-stigmastane-3,6-dione, β-sitosterol, ergosterol, stigmastane-3β,5α,6β-triol, stigmasta-3,5-dien-7-one, stigmast-4-en-3-one, β-stigmasterol, simiarenol, and 3β-hydroxystigmast-5-en-7-one [9, 20, 26, 29–31]. Guan’s group [9] have also reported the isolation of a steroidal glycoside named daucosterol from F. tikoua Bur,Figure 4
Structures of the steroids found inF. tikoua Bur.Table 4
Steroids isolated fromF. tikoua Bur.
No.Compound namesReference1053β-Hydroxystigmast-5-en-7-one[20]106β-Sitosterol[9, 20, 27]107Daucosterol[9]1085α-Stigmastane-3,6-dione[20]109Stigmastane-3β,5α,6β-triol[30]110Stigmasta-3,5-dien-7-one[31]111Stigmast-4-en-3-one[9, 31]112Ergosterol[31]113β-Stigmasterol[20, 27]


## 2.5. Other Compounds

Chemical compounds belonging to chemical classes other than previously mentioned have also been reported fromF. tikoua Bur. by multiple studies (Figure 5; Table 5). Wei et al. [15] isolated two benzofuran glycosides, 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside and 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-D-glucopyranoside, from the extract of F. tikoua Bur. stems. Similarly, another benzofuran glycoside, 6-(2-carboxyvinyl)-7-methoxy-5-hydroxy-benzofuran-5-O-β-D-glucopyranoside, was obtained by Wei et al. [19] from the water-soluble portion of the methanol extract of F. tikoua Bur. stems.Figure 5
Structures of some of other compounds found inF. tikoua Bur.Table 5
Other compounds found inF. tikoua Bur.
No.Compound namesReference1146-Carboxyethyl-5-hydroxybenzofuran[15]1155-O-β-D-glucopyranoside, 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside[15]1166-(2-Carboxyvinyl)-7-methoxy-5-hydroxy-benzofuran[19]1175-O-β-D-glucopyranoside (±)-ficunomone[17]118Angelicin[31]119Isobergapten[31]120Esculetin[26]121Indole-3-carboxylic acid[26]122Bergapten[9, 22, 29, 30, 32]1235,7-Dihydroxychromone[26]124Noreugenin[26]125Alloptaeroxylin[26]126Dimethyl phthalate[31]127Dibutyl phthalate[31]128Diisobutyl phthalate[31]129Dihexyl phthalate[31]130Marmesin[31]131Triethyl citrate[31]1322,6-Dimethoxy-1,4-benzoquinone[27]133Allantoin[9]134Neoechinulin A[26]Coumarins and chromones are oxygenated heterocyclic compounds that belong to the benzopyrone chemical class. Bergapten is the most common coumarin that has been isolated fromF. tikoua Bur. by more than one study [9, 22, 29, 30, 32]. Esculetin isolated by Zhou et al. [26] and nodakenin and psoralen isolated by He et al. [22] are other examples of coumarins presented in F. tikoua. Very recently, Zhou’s group [17, 26] reported isolation of one new and three chromone compounds from the aerial parts of F. tikoua: (±)-ficunomone, 5,7-dihydroxychromone, noreugenin, and alloptaeroxylin. They also reported the extraction of two alkaloids, neoechinulin A and indole-3-carboxylic acid, for the first time from F. tikoua Bur.Yang’s group [33] in 2016 investigated the F. tikoua Bur. fruit for the identification of volatile compounds. The authors detected the presence of 152 chemical compounds in F. tikoua Bur. fruits. Among these, esters, alcohols, and alkenes were prominent aroma components class accounting for 33.06%, 13.14%, and 13.18%, respectively, of the total aroma component detected in the F. tikoua Bur. fruits. The major aroma compounds found in the study were as follows: guaiacol, cyclobutane carboxylic acid dodecyl ester, n-tridecane, 2-tridecanone, cyclohexasiloxane, cyclobutanecarboxylic acid decyl ester, methyl nonyl ketone, and acetic acid.Many fatty acids (saturated and unsaturated both), fatty acid methyl esters, fatty acid ethyl esters, fatty acid butyl esters, fatty acid isopropyl esters, and fatty aldehydes have been reported fromF. tikoua Bur. extracts [28, 34]. Additionally, benzoquinone [27], imidazole [9], alpha-tocopherol [34], naphthalene [22], and numerous hydrocarbons (alkanes, alkenes, and styrene) have also been identified in F. tikoua Bur. Tian’s group [28] identified fifty-three compounds in the essential oil of F. tikoua Bur. by GC-FID/MS, and among the identified components, palmitic acid (51.13%) and linoleic acid (47.54%) were the major fraction.


## 3. Biological Activities ofF. tikoua Bureau

Crude extract ofF. tikoua Bur. and natural compounds isolated from it have been found to possess antioxidant, antibacterial, anti-inflammatory, antiviral, and antitumor activities.


### 3.1. Antimicrobial Effect

Xiang and Wang [35] used the agar plate diffusion method to quantitatively detect the antibacterial effect of F. tikoua Bur. water extract on gram-negative bacteria, Escherichia coli and Shigella dysenteriae, and gram-positive bacteria, Staphylococcus aureus. The results showed that F. tikoua Bur. water extract had a concentration-dependent antibacterial effect on Shigella dysenteriae and Staphylococcus aureus but had no effect on Escherichia coli. Wang et al. [36] used the conventional agar diffusion method to perform in vitro antibacterial tests of F. tikoua Bur. extract on Staphylococcus aureus, Escherichia coli, Candida albicans, Pseudomonas aeruginosa, and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) strains. The results showed that the extract had no obvious inhibitory effects on Staphylococcus aureus, Escherichia coli, Candida albicans, and Pseudomonas aeruginosa but had inhibitory effects on the four strains of clinically isolated MRSA. Yang et al. [14] determined the antibacterial activity of ethanol extract from F. tikoua Bur. roots by using the paper disc diffusion method. The authors found that 95% ethanol extract of F. tikoua Bur. roots had clear but weak inhibitory effects on five different bacteria, with the order of inhibition was as follows: Shigella flexneri > Bacillus megaterium > Proteus sp. > Pseudomonas aeruginosa > Micrococcus luteus.Wei et al. [18] conducted in vitro antifungal tests against Phytophthora infestans via spore germination assay for the compounds isolated from F. tikoua Bur: genistein, myrsininone A, wighteone, lupiwighteone, naringenin, and 8-prenylnaringenin. All isolated compounds except myrsininone A showed antifungal activity. The strongest antifungal activity against Phytophthora infestans was registered for naringenin, 8-prenylnaringenin, and 6-prenylnaringenin, with IC50 values of 10.447, 10.864, and 16.828 μg/mL, respectively [18]. In an another study, Wei et al. [37] isolated a new pyrano-isoflavone (5,3′,4′-trihydroxy-2″,2″-dimethylpyrano (5″, 6″ : 7, 8) isoflavone) from F. tikoua Bur. stems and reported that the compound possesses antifungal activity against Phytophthora infestans with an IC50 value of 262.442 μg/mL.Du [38] conducted in vitro antibacterial experiments on the water extract of F. tikoua Bur. against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Enterobacter aerogenes, Proteus sp., and Pseudomonas aeruginosa via Oxford cup method and agar dilution method. The F. tikoua Bur. extracts showed antibacterial activity against all tested bacteria except Escherichia coli. In the study of Tian et al. [28], the essential oil from F. tikoua Bur. revealed significant antibacterial activity in a microdilution assay against Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris. The values of zone of inhibition, minimal inhibitory concentration (MIC), and minimal bactericidal concentration (MBC) of essentials oils in the study were ranged from 7.89 to 10.59 mm, 0.20 to 6.25 mg/mL, and 0.20 to 12.50 mg/mL, respectively. Cheng et al. [39] studied the antibacterial effects of three different solvent extracts of F. tikoua: petroleum ether, ethyl acetate, and n-butanol. All three F. tikoua Bur. crude extracts exhibited antibacterial activities against Escherichia coli, Staphylococcus epidermidis, Shigella, and Staphylococcus aureus.Although none of these studies undertook mechanistic study of the antimicrobial effects shown byF. tikoua Bur. extracts and compounds isolated from it, as per existing literature plant extracts decrease cytoplasmic pH of bacterial cells and hyperpolarize the bacterial cell membrane, thus resulting in the disruption of cell wall, leakage of cytoplasmic contents, and ultimately the death of bacterial cells [40, 41]. Similarly, isoflavone biochanin A has previously been found to exert its antibacterial activities against MRSA, Chlamydia spp., and Mycobacterium strains by inhibiting their efflux pumps system [41]. Although the antibacterial activity of 3′-(3-methylbut-2-enyl)biochanin A, a biochanin A derivative isoflavone, isolated from F. tikoua Bur. was not studied by Wu et al. [32] and Zhou et al. [21], it is possible that this compound also has similar antibacterial activity and mechanism as that of biochanin A.


### 3.2. Antitumor Effect

Plant phenolic compounds show antitumor effects, which can be attributed to the presence of aromatic rings and hydroxyl groups in their structure. Presence of more than one hydroxyl group and short fatty acid side chain in certain plant phenolic compounds makes them more potent than phenolic compounds with only one hydroxyl group [42]. F. tikoua Bur. extracts have been shown to have cytotoxic properties against tumor cells; for example, in the study of Tian et al. [28], the essential oil from F. tikoua Bur. exhibited significant cytotoxicity against A549, NCI-H1299, PC-3, and K562 tumor cells, with IC50 values of 131.08, 50.32, 120.58, and 31.68 μg/mL, respectively. The essential oil exhibited selective cytotoxicity to human tumor cell lines, with a significantly lower cytotoxicity to human normal cells MRC-5 (IC50 = 161.75 μg/mL) than to tumor cells. Although, in literature, both fatty acids [42, 43] and terpenoids [44] have been shown to have antitumor activities, there is a possibility that majority of antitumor effect in the study of Tian et al. [28] could be due to palmitic acid and linoleic acid alone, but not from terpene compounds. The reason for it is that, in the essential oil extracted from F. tikoua Bur., major portion was of palmitic acid (51.13%) and linoleic acid (47.54%), whereas terpenes were only a minuscule amount in the essential oil.As mentioned previously, Jiang et al. [24] isolated ten phenolic glycosides (Table 2) from F. tikoua Bur. rhizomes. These phenolic glycosides were tested for their cytotoxic effects against HeLa, K562, HL60, and HepG2 cancer cell lines via MTT (3-(4,5-dimeth-ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All the phenolic glycosides showed a varying degree of antitumor effects against tested cancer cell lines. The IC50 values of phenolic glycosides against HeLa, K562, HL60, and HepG2 cells were ranged from 16.0 ± 3.2 to 79.2 ± 9.7 μM, 16.3 ± 3.8 to 102.5 ± 11.3 μM, 15.1 ± 5.4 to 89.8 ± 9.1 μM, and 15.1 ± 6.3 to 132.4 ± 10.8 μM, respectively.Tian et al. [30] tested the antitumor activities of compounds (bergapten, oleanolic acid, palmitic acid, β-amyrin palmitate, ursolic acid, nonacosane, germanicol acetate, triacontane acid, linoleic acid, stigmastane-3β,5α,6β-triol) extracted from F. tikoua Bur. against PC-3, K562, and A549 cell lines. The results showed that, among all extracted compounds from F. tikoua Bur. in the study, ursolic acid, which is a pentacyclic triterpene, had the highest cytotoxic activity against K562 with an IC50 value of 1.69 μg/mL, which was stronger than the positive control cisplatin (IC50 = 10.21 μg/mL). Ursolic acid has been widely studied for its anticancer property; and it has been reported that ursolic acid interacts with a number of signaling molecules in cell signaling pathways, and it checks cell proliferation and causes apoptosis of tumor cells [45].


### 3.3. Antioxidant Activities

F. tikoua Bur. is rich in many phytochemicals such as flavonoids, terpenes, and phenolic acids, and thus it is no surprise that many studies have found antioxidant properties in its extracts. Yang et al. [14] used the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method to determine the antioxidant activities of different solvent extracts (ethanol, ethyl acetate, and n-butanol extracts) of F. tikoua Bur. roots. All extracts showed concentration-dependent strong DPPH free radical scavenging ability. Wei et al. [15] isolated two benzofuran glucosides, 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-D-glucopyranoside and 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside, from F. tikoua Bur. and found antioxidant activities for both the compounds with IC50 values of 242.8 and 324.9 μg/mL, respectively. Fu’s group [16] investigated the free radical scavenging activity of five isoflavones and one flavonol isolated from F. tikoua Bur. (ficusin C, 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavone, ficusin A, alpinumisoflavone, 4′-O-methylalpinumisoflavone, and quercetin) and reported that the EC50 values of the six compounds were 49.3 ± 7.8, 43.3 ± 6.9, 42.4 ± 6.6, 54.8 ± 9.7, and 83.6 ± 12.5, 4.2 ± 0.5, respectively. As it is clearly seen by the EC50 values, among all six flavonoids, flavonol quercetin showed the maximum antioxidant capability, more than any other isoflavones in the experiment. It is because the total number of hydroxyl groups is one of the important factors for the flavonoid to be a potent antioxidant [46], and among the six flavonoids, quercetin had the maximum number of hydroxyl groups.Cheng et al. [39] studied the free radical scavenging activity of the three different solvent extracts of F. tikoua Bur. The authors found that all three extracts could scavenge DPPH, hydroxyl, and superoxide free radicals in a concentration-dependent manner. He’s group [22] isolated total seventeen chemical compounds of different classes (isoflavones, flavanols, coumarin, lignan, and neolignan) from F. tikoua Bur. and examined their DPPH radical scavenging rate, total antioxidant capacity, and superoxide anion scavenging capacity. Among all 17 isolated compounds from F. tikoua Bur., the following compounds were found to have significant antioxidant activity: ssioriside, huazhongilexin, 6,7-dimethoxy-4-hydroxy-1-naphthoic acid, ethy-3,4-dihydroxybenzoate, and 3,3′,4,4′-tetrahydroxy diphenyl.


### 3.4. Anti-Inflammatory Effect

Li et al. [47] in the study on 24 Australian and Chinese plants for their anti-inflammatory properties found moderate inhibition of cyclooxygenase-1 (COX-1) by ethanol extracts from F. tikoua Bur. stem, thus confirming its use as a traditional medicine in China for many diseases such as arthritis, edema, infections, and snakebite. Similarly, to find the plants having potential anti-inflammatory activities, Liao et al. [48] investigated many traditional Chinese herbs species for their effect on nitric oxide (NO) production in a murine macrophage-like cell line, RAW 264.7, which was activated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). F. tikoua Bur. was also one of the plants that were tested in this study. Extract prepared from syconium of F. tikoua Bur. showed significant inhibition of NO production by activated macrophage with an IC50 value of 17.51 μg/mL. The results suggested possible anti-inflammatory effect of F. tikoua. Inhibition of nitric oxide production appears to be the standard mechanism for the anti-inflammatory effect shown by F. tikoua Bur. because other studies have also proposed similar mechanism (that is inhibition of NO production by LPS-induced RAW 264.7 macrophage cells) for other plant-derived and commercially sourced phenolic compounds like kaempferol and its glycosides [49, 50].


### 3.5. Antidiabetic Effect

F. tikoua Bur. has also been reported to have a potential role against diabetes [16, 32]. The latest research by Zhou et al. [17] found that seven flavonoids isolated from F. tikoua Bur. could inhibit a-glucosidase, among which 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]5,7,4′-trihydroxyisoflavone and ficusin A exhibited the highest inhibitory activity, with IC50 values at 5.12 ± 0.10 and 3.43 ± 0.15 μM, respectively. Wu’s group [32] isolated nine compounds from F. tikoua Bur. and tested their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), which plays an important role in insulin signaling, thus investigating possible antidiabetic action of F. tikoua Bur. In the study, isoprenylated flavonoids were found to inhibit PTP1B (IC50 = 11.16–40.37 μM), whereas compounds without isoprenoid group, flavonoid genistein and coumarin bergapten, were inactive against PTP1B. This study supports the previous findings that the prenylation of flavonoids increases their inhibitory activity against PTP1B compared with the nonprenylated flavonoids [51, 52]. Similarly, Fu’s group [16] found α-glucosidase inhibitory activity and thus antidiabetic potential for all flavonoid compounds isolated from F. tikoua Bur. in the study (ficusin C, 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavone, ficusin A, alpinumisoflavone, 4′-O-methylalpinumisoflavone, and quercetin) with IC50 values of 62.4 ± 6.9, 32.5 ± 6.7, 84.6 ± 7.8, 73.3 ± 12.9, 85.4 ± 11.5, and 31.2 ± 5.7 μM, respectively.


### 3.6. Other Biological Effects

We found only a single study on the antiviral effect ofF. tikoua. Zhang et al. [53] used respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), coxsackievirus (COX-B5), and enterovirus 71 (EV71) to study the in vitro antiviral activity of different solvent extracts of F. tikoua. The results showed that the ethyl acetate extract had weak antiviral effects on EV71 and HSV-1, whereas the water extract of F. tikoua Bur. exhibited significant antiviral effects against COX-B5 and RSV.Xiong and Li [54] investigated the effect of the different F. tikoua Bur. extracts on the tyrosinase activity. The results showed that the extracts had strong activation effect on tyrosinase, and the activation effect did not change linearly with the increase of concentration. The ethyl acetate extract had different activation effects on tyrosinase, and the active components in the extract had noncompetitive activation and mixed activation effects on tyrosinase. The study showed the therapeutic potential of F. tikoua Bur. in the treatment of skin hypopigmentation.


## 3.1. Antimicrobial Effect

Xiang and Wang [35] used the agar plate diffusion method to quantitatively detect the antibacterial effect of F. tikoua Bur. water extract on gram-negative bacteria, Escherichia coli and Shigella dysenteriae, and gram-positive bacteria, Staphylococcus aureus. The results showed that F. tikoua Bur. water extract had a concentration-dependent antibacterial effect on Shigella dysenteriae and Staphylococcus aureus but had no effect on Escherichia coli. Wang et al. [36] used the conventional agar diffusion method to perform in vitro antibacterial tests of F. tikoua Bur. extract on Staphylococcus aureus, Escherichia coli, Candida albicans, Pseudomonas aeruginosa, and clinically isolated methicillin-resistant Staphylococcus aureus (MRSA) strains. The results showed that the extract had no obvious inhibitory effects on Staphylococcus aureus, Escherichia coli, Candida albicans, and Pseudomonas aeruginosa but had inhibitory effects on the four strains of clinically isolated MRSA. Yang et al. [14] determined the antibacterial activity of ethanol extract from F. tikoua Bur. roots by using the paper disc diffusion method. The authors found that 95% ethanol extract of F. tikoua Bur. roots had clear but weak inhibitory effects on five different bacteria, with the order of inhibition was as follows: Shigella flexneri > Bacillus megaterium > Proteus sp. > Pseudomonas aeruginosa > Micrococcus luteus.Wei et al. [18] conducted in vitro antifungal tests against Phytophthora infestans via spore germination assay for the compounds isolated from F. tikoua Bur: genistein, myrsininone A, wighteone, lupiwighteone, naringenin, and 8-prenylnaringenin. All isolated compounds except myrsininone A showed antifungal activity. The strongest antifungal activity against Phytophthora infestans was registered for naringenin, 8-prenylnaringenin, and 6-prenylnaringenin, with IC50 values of 10.447, 10.864, and 16.828 μg/mL, respectively [18]. In an another study, Wei et al. [37] isolated a new pyrano-isoflavone (5,3′,4′-trihydroxy-2″,2″-dimethylpyrano (5″, 6″ : 7, 8) isoflavone) from F. tikoua Bur. stems and reported that the compound possesses antifungal activity against Phytophthora infestans with an IC50 value of 262.442 μg/mL.Du [38] conducted in vitro antibacterial experiments on the water extract of F. tikoua Bur. against Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Enterobacter aerogenes, Proteus sp., and Pseudomonas aeruginosa via Oxford cup method and agar dilution method. The F. tikoua Bur. extracts showed antibacterial activity against all tested bacteria except Escherichia coli. In the study of Tian et al. [28], the essential oil from F. tikoua Bur. revealed significant antibacterial activity in a microdilution assay against Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Proteus vulgaris. The values of zone of inhibition, minimal inhibitory concentration (MIC), and minimal bactericidal concentration (MBC) of essentials oils in the study were ranged from 7.89 to 10.59 mm, 0.20 to 6.25 mg/mL, and 0.20 to 12.50 mg/mL, respectively. Cheng et al. [39] studied the antibacterial effects of three different solvent extracts of F. tikoua: petroleum ether, ethyl acetate, and n-butanol. All three F. tikoua Bur. crude extracts exhibited antibacterial activities against Escherichia coli, Staphylococcus epidermidis, Shigella, and Staphylococcus aureus.Although none of these studies undertook mechanistic study of the antimicrobial effects shown byF. tikoua Bur. extracts and compounds isolated from it, as per existing literature plant extracts decrease cytoplasmic pH of bacterial cells and hyperpolarize the bacterial cell membrane, thus resulting in the disruption of cell wall, leakage of cytoplasmic contents, and ultimately the death of bacterial cells [40, 41]. Similarly, isoflavone biochanin A has previously been found to exert its antibacterial activities against MRSA, Chlamydia spp., and Mycobacterium strains by inhibiting their efflux pumps system [41]. Although the antibacterial activity of 3′-(3-methylbut-2-enyl)biochanin A, a biochanin A derivative isoflavone, isolated from F. tikoua Bur. was not studied by Wu et al. [32] and Zhou et al. [21], it is possible that this compound also has similar antibacterial activity and mechanism as that of biochanin A.


## 3.2. Antitumor Effect

Plant phenolic compounds show antitumor effects, which can be attributed to the presence of aromatic rings and hydroxyl groups in their structure. Presence of more than one hydroxyl group and short fatty acid side chain in certain plant phenolic compounds makes them more potent than phenolic compounds with only one hydroxyl group [42]. F. tikoua Bur. extracts have been shown to have cytotoxic properties against tumor cells; for example, in the study of Tian et al. [28], the essential oil from F. tikoua Bur. exhibited significant cytotoxicity against A549, NCI-H1299, PC-3, and K562 tumor cells, with IC50 values of 131.08, 50.32, 120.58, and 31.68 μg/mL, respectively. The essential oil exhibited selective cytotoxicity to human tumor cell lines, with a significantly lower cytotoxicity to human normal cells MRC-5 (IC50 = 161.75 μg/mL) than to tumor cells. Although, in literature, both fatty acids [42, 43] and terpenoids [44] have been shown to have antitumor activities, there is a possibility that majority of antitumor effect in the study of Tian et al. [28] could be due to palmitic acid and linoleic acid alone, but not from terpene compounds. The reason for it is that, in the essential oil extracted from F. tikoua Bur., major portion was of palmitic acid (51.13%) and linoleic acid (47.54%), whereas terpenes were only a minuscule amount in the essential oil.As mentioned previously, Jiang et al. [24] isolated ten phenolic glycosides (Table 2) from F. tikoua Bur. rhizomes. These phenolic glycosides were tested for their cytotoxic effects against HeLa, K562, HL60, and HepG2 cancer cell lines via MTT (3-(4,5-dimeth-ylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. All the phenolic glycosides showed a varying degree of antitumor effects against tested cancer cell lines. The IC50 values of phenolic glycosides against HeLa, K562, HL60, and HepG2 cells were ranged from 16.0 ± 3.2 to 79.2 ± 9.7 μM, 16.3 ± 3.8 to 102.5 ± 11.3 μM, 15.1 ± 5.4 to 89.8 ± 9.1 μM, and 15.1 ± 6.3 to 132.4 ± 10.8 μM, respectively.Tian et al. [30] tested the antitumor activities of compounds (bergapten, oleanolic acid, palmitic acid, β-amyrin palmitate, ursolic acid, nonacosane, germanicol acetate, triacontane acid, linoleic acid, stigmastane-3β,5α,6β-triol) extracted from F. tikoua Bur. against PC-3, K562, and A549 cell lines. The results showed that, among all extracted compounds from F. tikoua Bur. in the study, ursolic acid, which is a pentacyclic triterpene, had the highest cytotoxic activity against K562 with an IC50 value of 1.69 μg/mL, which was stronger than the positive control cisplatin (IC50 = 10.21 μg/mL). Ursolic acid has been widely studied for its anticancer property; and it has been reported that ursolic acid interacts with a number of signaling molecules in cell signaling pathways, and it checks cell proliferation and causes apoptosis of tumor cells [45].


## 3.3. Antioxidant Activities

F. tikoua Bur. is rich in many phytochemicals such as flavonoids, terpenes, and phenolic acids, and thus it is no surprise that many studies have found antioxidant properties in its extracts. Yang et al. [14] used the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method to determine the antioxidant activities of different solvent extracts (ethanol, ethyl acetate, and n-butanol extracts) of F. tikoua Bur. roots. All extracts showed concentration-dependent strong DPPH free radical scavenging ability. Wei et al. [15] isolated two benzofuran glucosides, 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-D-glucopyranoside and 6-carboxyethyl-7-methoxyl-5-hydroxy-benzofuran 5-O-β-D-glucopyranoside, from F. tikoua Bur. and found antioxidant activities for both the compounds with IC50 values of 242.8 and 324.9 μg/mL, respectively. Fu’s group [16] investigated the free radical scavenging activity of five isoflavones and one flavonol isolated from F. tikoua Bur. (ficusin C, 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavone, ficusin A, alpinumisoflavone, 4′-O-methylalpinumisoflavone, and quercetin) and reported that the EC50 values of the six compounds were 49.3 ± 7.8, 43.3 ± 6.9, 42.4 ± 6.6, 54.8 ± 9.7, and 83.6 ± 12.5, 4.2 ± 0.5, respectively. As it is clearly seen by the EC50 values, among all six flavonoids, flavonol quercetin showed the maximum antioxidant capability, more than any other isoflavones in the experiment. It is because the total number of hydroxyl groups is one of the important factors for the flavonoid to be a potent antioxidant [46], and among the six flavonoids, quercetin had the maximum number of hydroxyl groups.Cheng et al. [39] studied the free radical scavenging activity of the three different solvent extracts of F. tikoua Bur. The authors found that all three extracts could scavenge DPPH, hydroxyl, and superoxide free radicals in a concentration-dependent manner. He’s group [22] isolated total seventeen chemical compounds of different classes (isoflavones, flavanols, coumarin, lignan, and neolignan) from F. tikoua Bur. and examined their DPPH radical scavenging rate, total antioxidant capacity, and superoxide anion scavenging capacity. Among all 17 isolated compounds from F. tikoua Bur., the following compounds were found to have significant antioxidant activity: ssioriside, huazhongilexin, 6,7-dimethoxy-4-hydroxy-1-naphthoic acid, ethy-3,4-dihydroxybenzoate, and 3,3′,4,4′-tetrahydroxy diphenyl.


## 3.4. Anti-Inflammatory Effect

Li et al. [47] in the study on 24 Australian and Chinese plants for their anti-inflammatory properties found moderate inhibition of cyclooxygenase-1 (COX-1) by ethanol extracts from F. tikoua Bur. stem, thus confirming its use as a traditional medicine in China for many diseases such as arthritis, edema, infections, and snakebite. Similarly, to find the plants having potential anti-inflammatory activities, Liao et al. [48] investigated many traditional Chinese herbs species for their effect on nitric oxide (NO) production in a murine macrophage-like cell line, RAW 264.7, which was activated by lipopolysaccharide (LPS) and interferon-γ (IFN-γ). F. tikoua Bur. was also one of the plants that were tested in this study. Extract prepared from syconium of F. tikoua Bur. showed significant inhibition of NO production by activated macrophage with an IC50 value of 17.51 μg/mL. The results suggested possible anti-inflammatory effect of F. tikoua. Inhibition of nitric oxide production appears to be the standard mechanism for the anti-inflammatory effect shown by F. tikoua Bur. because other studies have also proposed similar mechanism (that is inhibition of NO production by LPS-induced RAW 264.7 macrophage cells) for other plant-derived and commercially sourced phenolic compounds like kaempferol and its glycosides [49, 50].


## 3.5. Antidiabetic Effect

F. tikoua Bur. has also been reported to have a potential role against diabetes [16, 32]. The latest research by Zhou et al. [17] found that seven flavonoids isolated from F. tikoua Bur. could inhibit a-glucosidase, among which 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]5,7,4′-trihydroxyisoflavone and ficusin A exhibited the highest inhibitory activity, with IC50 values at 5.12 ± 0.10 and 3.43 ± 0.15 μM, respectively. Wu’s group [32] isolated nine compounds from F. tikoua Bur. and tested their inhibitory activities against protein tyrosine phosphatase 1B (PTP1B), which plays an important role in insulin signaling, thus investigating possible antidiabetic action of F. tikoua Bur. In the study, isoprenylated flavonoids were found to inhibit PTP1B (IC50 = 11.16–40.37 μM), whereas compounds without isoprenoid group, flavonoid genistein and coumarin bergapten, were inactive against PTP1B. This study supports the previous findings that the prenylation of flavonoids increases their inhibitory activity against PTP1B compared with the nonprenylated flavonoids [51, 52]. Similarly, Fu’s group [16] found α-glucosidase inhibitory activity and thus antidiabetic potential for all flavonoid compounds isolated from F. tikoua Bur. in the study (ficusin C, 6-[(1R∗, 6R∗)-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5,7,4′-trihydroxyisoflavone, ficusin A, alpinumisoflavone, 4′-O-methylalpinumisoflavone, and quercetin) with IC50 values of 62.4 ± 6.9, 32.5 ± 6.7, 84.6 ± 7.8, 73.3 ± 12.9, 85.4 ± 11.5, and 31.2 ± 5.7 μM, respectively.


## 3.6. Other Biological Effects

We found only a single study on the antiviral effect ofF. tikoua. Zhang et al. [53] used respiratory syncytial virus (RSV), herpes simplex virus (HSV-1), coxsackievirus (COX-B5), and enterovirus 71 (EV71) to study the in vitro antiviral activity of different solvent extracts of F. tikoua. The results showed that the ethyl acetate extract had weak antiviral effects on EV71 and HSV-1, whereas the water extract of F. tikoua Bur. exhibited significant antiviral effects against COX-B5 and RSV.Xiong and Li [54] investigated the effect of the different F. tikoua Bur. extracts on the tyrosinase activity. The results showed that the extracts had strong activation effect on tyrosinase, and the activation effect did not change linearly with the increase of concentration. The ethyl acetate extract had different activation effects on tyrosinase, and the active components in the extract had noncompetitive activation and mixed activation effects on tyrosinase. The study showed the therapeutic potential of F. tikoua Bur. in the treatment of skin hypopigmentation.


## 4. Conclusion

The present review provides an overview of the previous and current research on chemical compounds isolated fromF. tikoua Bur. and summarizes their biological activities. In summary, many natural compounds of varied chemical classes have been isolated from different parts of F. tikoua Bur. (stems, roots, whole plant, aerial parts, and syconium) and have been found in various in vitro experiments to possess antimicrobial (antibacterial and antifungal), antiviral, antioxidant, antidiabetic, antitumor, and anti-inflammatory properties. These studies not only confirm the traditional usage of F. tikoua but also elucidate its new applications. Despite this, as can be concluded from this review, there are only few studies on chemical constituents of F. tikoua Bur. and its biological effects. Additionally, the lack of mechanistic study on the biological effects of F. tikoua Bur. is another research area that demands attention because understanding the mechanism of biological effects of medicinal plant extracts is the first step in their utilization for therapeutic application. Further research on the phytochemical and pharmacological aspects of F. tikoua Bur. should be pursued. Moreover, the biological activities of F. tikoua Bur. have been tested only in in vitro settings. Phytochemicals from F. tikoua Bur. further needs to be studied in in vivo conditions for their therapeutic potential so that this traditional medicine can be brought to the new horizon of modern medicine.



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*Source: 2423525-2022-08-25.xml*