Phytochemical composition and medicinal potential

This review aims to gather information on chemical compounds, biological activities and patents concerning parts of Ficus species, in order to contribute to the design of future studies. Systematic research was carried out on databases over the last five years. A total of 103 papers and 11 patents were found. Several species were investigated considering their chemical composition and biological properties. Organic acids, phenolic compounds, flavonoids, and terpenes were identified. Ficus carica was the most investigated species of the genus. Antioxidant, antimicrobial, antihyperglycemic, antidiabetes, anticancer and cytotoxic were the main reported activities, revealing their natural supplementary potential in contemporary diseases. Some of their chemical constituents presented pharmacological properties. These results suggest the potential of extracts and essential oil of Ficus genus in pharmacological industry. More studies still need to identify the compounds related to each property. Patents concerning parts of Ficus spp. involve different application areas, mainly cosmetics, food and pharmacology. This review may inspire investigations considering the development of new drugs, as well as new scientific and technological research using different parts of the Ficus genus.

We previously reviewed the chemical composition, properties and products of Ficus spp (Cruz et al., 2022). In the present review we aim at the scientific contribution on the other plant parts of Ficus spp. to facilitate the understanding of the importance of the genus, direct future studies from its chemical constituents and biological activities, as well as enhance the development of new products from the macro view the use of its patented products.

Search Methodology
This review was searched in Scopus, ScienceDirect, Capes Periodicals and Google Schoolar databases. Search was performed using term "Ficus" together with "biological activity", "properties", "biological potential", "medicinal", "phytochemical", "chemical compounds" and "composition", considering published papers from 2016 to 2021. The review in patent databases such as INPI, SPACENET, USTPO, PATENTSCOPE also pointed, considering the last five years, to species of the Ficus genus, as well as the use of their specific Booleans. The method addressed the use of chemical compounds and proven properties in different areas of application using plant parts of Ficus species.

Phytochemical content
Different classes of compounds were identified in bark, roots and aerial parts of the species from the Ficus genus, predominantly alkaloids, flavonoids, glycosides, saponins, steroids, tanins and terpenes. The variety of phytochemicals is essential for the development of new products, so it is described in Table 1.

Phenolic compounds
Phenolic compounds were identified in all parts of Ficus, as shown in Table 2. The ellagic acid was found in the leaves of F. capensis, F. palmata and F. sycomorus (Akomolafe et al., 2016;El-Beltagi et al., 2019;Shaheen & Ahmad, 2021).

Terpenes, steroids and fatty acids
A mixture of linear aliphatic alkanes (the steroids β-sitosterol and sitosteryl 3-O-β-D-glucopyranoside and other constituents) was identified in the raw chloroformic/ethanolic extract of the wood from aerial roots of F. elastica (J. M. E. Teinkela, Noundou, et al., 2016). In the essential oils of the leaves of F. capensis were identified mainly fatty acids and alkanes (Lawal et al., 2016). In the latex of F. carica a mixture of saturated and unsaturated fatty acids was reported (Ghanbari et al., 2019).

Antioxidant activity
Among the species from the Ficus genus, antioxidant activity was reported by alcoholic, aqueous, hydroalcoholic, hexane and chloroform, ethyl acetate, dichloromethane and petroleum ether extracts from different parts, such as leaves, bark, branches, stem and roots, mainly by in vitro assays, as presented in Table 3. In general, polar extracts (such as alcoholic and hydroalcoholic) revealed compounds responsible for antioxidant activity. Hot water is a good solvent strategy, as it has improved the extraction of antioxidant compounds in roots from F. dubia (Suttisansanee et al., 2021).  (Misso et al., 2020) Source: Authors.
Some reports compared the extraction of phenolic compounds and antioxidant activity by conventional and ultrasound-assisted methods. The best antioxidant activity was observed in leaf extracts (Alcántara et al., 2020), and látex  of F. carica obtained from conventional method.
The methanol extract of F. racemosa leaves showed antioxidant activity through radical scavenging (DPPH˙, O2˙ and OH˙) and Reducing Power Assay similar to the fruit extract (Sumi et al., 2016). On the other hand, extracts from ethanol, toluene e ethyl acetate of the fruits presented antioxidant activity superior to the leaves. For both parts, the toluene extract showed the best results, with IC50 of (0.75 ± 0.01) µg/mL for fruits and (2.35 ± 0.41) µg/mL for leaves (Bagyalakshmi et al., 2019).
Methanol and chloroform extracts from F. sycomorus leaves showed statistically similar percentages of inhibition of DPPH˙ radicals of 47 ± 2.17 and 42 ± 0.13, respectively. However, the fruit extracts were more active (Ozdenefe et al., 2020).
On the other hand, the ethanol and ethyl acetate extracts from the leaves were slightly higher in antioxidant potential than the fruits (El-Beltagi et al., 2019).
The CH2Cl2:EtOH extract of F. sycomorus bark showed better antioxidant activity when compared to the same leaf extract and hexane extracts from leaves and stem bark. In the ABTS and DPPH˙ assays, its activity was 40.81 ± 1.15 and 32.87 ± 0.71 mg TE/g, respectively (Suliman et al., 2021). The aqueous extract of F. vogeliana bark also showed good antioxidant potential, with IC50 of 4.60 ± 0.15 μg/mL and antioxidant activity index (AAI) of 10.88 ± 0.36 in DPPH˙ tests, which were statistically similar to vitamin C (Misso et al., 2020).
In vitro assays were predominantly used to measure antioxidant potential. The ethanol extract of F. carica leaves caused a reduction of malondialdehyde (MDA) in in vivo tests, a marker of oxidative stress (Sukowati et al., 2019). Moreover, the hydroethanol extract (70:30, v/v) of aerial parts of F. religious showed potential to normalize the levels of antioxidant enzymes (CAT and SOD) (Singh et al., 2020). Chloroform extract of F. glomerata leaves reduced the oxidative stress in diabetic rats (Shaikh et al., 2020).
Research suggests that extracts from different parts of Ficus spp. exhibit antioxidant activity, both in vitro and in animal model. However, it is suggested for the future, in vivo tests also using fractions to guide the isolation of compounds with biological interest.

Antimicrobial activity
The essential oil and extracts from the parts of Ficus spp. presented activity against microorganisms, such as C.
The methanol extract of F. elastica roots showed lower antimicrobial activity when compared to gentamycin and fluconazole controls (MIC, 25 μg/mL) against fungi and gram-positive and gram-negative bacteria. However, some isolated compounds showed good antimicrobial activity. Ficusoside B presented a MIC of 4.9 μg/mL against E. coli, P. vulgaris, S.
Ficusnotanone and diarylbutanoids (Ficusnotins A-F) extracted from the ethanol extract of the leaves of F. nota, showed antibacterial activity against B. subtilis Latayada, Uy, Akihara, Ohta, Nehira, et al., 2017). We did not identify work in recent years testing antimicrobial activity in vivo. In addition, there are few Research, Society andDevelopment, v. 11, n. 12, e265111234135, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i12.34135 32 reports where purified compounds were tested for this activity, so this should be the focus of some future studies aimed at the discovery and development of new drugs. Table 5 shows the anti-hyperglycemic, andiabetes and antiobesogenic activities of different extract of Ficus genus.

Anti-hyperglycemic, andiabetes and antiobesogenic activities
These activities were also presented by some compounds isolated from species of this genus. Cycloartenol and 24methylenecycloartanol triterpenes isolated from the hexane extract of the stem bark of F. krishnae showed anti-hyperglycemic activity in rats (Sadasivan Nair et al., 2020), while four flavonoids, similar to kaempherol, quercetin, naringenin and baicalein, which were isolated from the hydromethanol extract of the stem bark of F. racemosa, showed antidiabetic and hypolipidemic activity in diabetic rats (Keshari et al., 2016). Inhibition of α-amylase, α-glucosidase and pancreatic lipase in vitro show their antidiabetic and antiobesogenic potential. (Mopuri et al., 2018) Leaf AcOEt It showed a significant effect on carbohydrate metabolism enzymes (glucose-6-phosphatase, fructose-1,6bisphosphatase and hexokinase) and reduced glucose, cholesterol and triglycerides levels. (Irudayaraj et al., 2017) Leaf

MeOH
Inhibition of pore opening, and reduction in levels of malondialdehyde and serum blood glucose. It has therapeutic potential for the treatment of diabetes. (Oyebode et al., 2019) Source: Authors.
F. asperifolia showed antidiabetic effects in rats induced by streptozotocin. The ethanol extract of leaves (400 mg/kg body weight) showed statistically similar effects to metglim (3.38 mg/kg body weight) on lipid profile (total cholesterol, high density lipoprotein, low density lipoprotein and triacylglyceride) and body weight diabetic rats (Pwaniyibo et al., 2020).
The aqueous extract, in addition to anti-hyperglycemic potential, showed profertility effect in diabetic male rats (Abu Bakar et al., 2020).
The ethanol extract of F. deltoidea leaves contributed to suppression of hypercholesterolemic induced in rats (Chuo et al., 2020). Its methanolic extract reduced glucose levels in diabetic rats and prevented diabetic osteoporosis through inhibition of bone oxidative stress (Samsulrizal et al., 2021).

Anticancer and cytotoxic activities
The anticancer and cytotoxic activities were reported in extracts and essential oil of the Ficus genus ( 34 cytotoxic effect against breast cancer cell lines (Al-Khdhairawi et al., 2017). A homogeneous pectic polysaccharide (FP2) isolated from the ethanol extract of the aerial parts of F. pandurata showed anticancer potential (Lv et al., 2020).
Proanthocyanidins isolated from the bark and leaves of F. virens showed cytotoxic activity against breast cancer cells (Chen et al., 2017). DMBA-induced skin cancer in rats. (Misso et al., 2020) Source: Authors.

Anti-inflammatory and healing properties
The aqueous and hydroethanolic extract of F. carica leaves showed anti-inflammatory activity in vitro, which was investigated using the cell-reporter plasmid pNiFty2-SEAP in HT-29 cells (human colon adenocarcinoma). Prominent results were presented by the hydroethanolic extract (Alcántara et al., 2020).
The ethanol extracts of the bark and roots of F. hirta and its fractions (CHCl3, AcOEt, BuOH) showed significant anti-inflammatory activity by inhibiting LPS-induced NO production in murine macrophage RAW264.7 (Cheng, Yi, Chen, et al., 2017;. Phenolic compounds isolated from the CHCl3 fraction of the roots also showed significant inhibition of NO production, including vanillin, (-)-pinoresinol and 30-hydroxy-40-methoxy-trans-cinnamaldehyde, which revealed their anti-inflammatory potential .
The ethanolic extract of the bark of F. hispida showed anti-inflammatory activity in rats (Howlader et al., 2017).
Ficuhismine B, an alkaloid isolated from the ethanol extract of branches and leaves, showed anti-inflammatory activity in vitro through the NF-κB pathway luciferase assay (Jia et al., 2020). The ethanolic and hydroethanolic extracts of the stem bark of F. palmata presented anti-inflammatory activity in vitro, through the inhibition of pro-inflammatory cytokines and by the negative regulation of pro-inflammatory mediators (Khajuria et al., 2018).
Dichloromethane and hexane extracts from the bark of F. racemosa showed healing activity in vitro, which was evidenced by increased cell migration, mainly attributed to the isolated compounds, lupeol and β-sitosterol (Bopage et al., 2018). The compound drupin, a cysteine protease isolated from the latex of F. drupacea, showed activity by accelerating the healing process in mice (Manjuprasanna et al., 2020).

Other reported activities
The aqueous extract of Ficus spp. presented different activities. The aerial roots of F. benghalensis showed improvement in memory, anxiolytic activity, muscle relaxant capacity and delay in the onset of seizures in mice. However, no significant effects on the sleep of the animals tested were identified (Panday & Rauniar, 2016). In F. carica leaves, cell cultures showed relief from skin damage caused by psychological stress in vitro and in vivo, suggesting its potential application in skin care products (Dini et al., 2021), a profertilizing effect was observed through the increase in the number of sperm in male diabetic rats (Abu Bakar et al., 2020). Potential to cure polycystic ovary syndrome in rats were observed in the F. religious leaves (Suriyakalaa et al., 2021). Oral supplementation of male mice with leaf extract significantly reduced neuromuscular coordination, exploratory behavior and object recognition ability (Akhtar et al., 2020).
The methanolic extract of F. deltoidea leaves improved the learning ability in rats through its oral administration, being related to the reduction of oxidative stress and, possibly, the reduction of sugar levels in the brain of the animals tested Research, Society and Development, v. 11, n. 12, e265111234135, 2022 (CC BY 4.0) (Nurdiana et al., 2018). The methanolic extract of F. platyphylla stem bark presented analgesic potential and neuroleptic effect in mice (Chindo et al., 2016;Sutter et al., 2019). The methanolic extract of F. dalhousiae stem bark was shown to be an antihyperlipidemic agent in hyperlipidemic rats induced a high fat diet (Surya et al., 2017). The methanol extract of F. elastica root wood demonstrated antitrypanosomal property, antimalarial activity and low in vitro cytotoxicity (J. M. E. Teinkela et al., 2018).
The ethanol extract of the stem bark of F. carica and its fraction rich in oligosaccharides presented neuroactivity and can significantly control the convulsive disorders induced by strychnine in male mice (Raafat & Wurglics, 2019).
Antinociceptive and sedative activity in rats were observed in ethanol extract of the bark of F. hispida showed (Howlader et al., 2017).
Immunomodulating property in vitro were identified in the methanol extract of the stem bark of F. glomerata, which was related to the presence of β-sitosterol and tannins identified in the extract (Heroor et al., 2020). Gastroprotective activity by inhibiting ulcers in rats were showed in the methanol extracts of the stem bark and leaves of F. glumosa. Furthermore, the leaves extract showed the most relevant results. This activity was related to isoquercitrin, hyperosid and p-hydroxybenzoic acid isolated in the species (G. V. Awolola et al., 2019).
Hepatoprotective effect were showed by methanol extract of F. carica leaves (Dureshahwar et al., 2019), and hydroethanolic extract of the leaves of F. spragueana in rats (El-hawary et al., 2019). The hydroethanolic extract of the aerial part of F. religious and methanol extract of F. carica leaves showed nephroprotective activity in diabetic rats (Dureshahwar et al., 2019;Singh et al., 2020).

Patents with Ficus spp.
The selected patents addressed the use of chemical compounds and properties in different areas of application, using parts of plants of the Ficus genus. Among the patents using Ficus spp. its use in the preparation of food products is contained, as a meat tenderizer, but in addition to its application for processing, it can also be a source for future patents in the food industry using the potential of bioactive compounds of species of this genus, such as functional teas. Other patents deal with topical and hair care and protection, which points to the potential of this genus in the preparation of cosmetics. Table 7 presents these and other patents using plant parts of the Ficus genus.

Country Summary Reference China
Refers to a sunscreen prepared with rich pectin components in Ficus pumila seed extract. (Aihua, 2017)

United States
Refers to compositions that include combinations of plant extracts (Ficus tikoua and others). Used as topical skin compositions, edible compositions, hair care compositions, etc. (Florence et al., 2017) China Provides a method of processing meat dumplings tenderized with ficin extracted of Ficus sp. Latex, belongs to the field of meat products processing technology.

Korea
Refers to a composition to prevent, improve or treat cognitive impairment, contains Ficus erecta extract as active ingredient. (Jeong et al.,

2018) China
Discloses a preparation method and application of a novel isoflavone compound extracted from Ficus auriculata. The compound has good effect of inhibiting the proliferation of three tumor cells. (Changri et al., 2018) China Belongs to the technical fields of tea, more particularly to a kind of functional tea with parts of the Ficus tikouae leaf for the treatment of enteritis. (Yuanxing, 2018)

China
Belong to the field of Chinese medicine, discloses a type of instant particles and its method of preparation for the treatment of renal edema with latex pulp, fruits and roots of Ficus sarmenosa and Ficus pumila. (Jie et al., 2018) China Provides a probiotic and edible medicinal tea drink of traditional Chinese medicine for the prevention of cancer and its method of preparation, the drink comprises parts of F. carica and other plants. (Wei, 2020) China It relates to a preparation method of freeze-dried powder of a composition with acne removing effect, with traditional Chinese medicine extract, Ficus pumila cryptocephala extract and others plants. (Renpu, 2020) Source: Authors.

Conclusions and Future Scope
The genus review enabled the macro vision of the state of the art, as well as the use of the Ficus genus in different areas such as: cosmetics, sunscreens, food technology, teas, softeners, probiotics, stem cell biotechnology, deficiency pharmacology cognitive impairment, tumor cell growth inhibitors, acne removers and in traditional Chinese medicine. This paper may contribute to the direction of future scientific and technological research using the different parts of the Ficus genus.
The results obtained in this review are related to the chemical knowledge of the Ficus genus, highlighting phenolic compounds and flavonoids as the main bioactive compounds responsible for most of the activities, such as antioxidants and antimicrobials. The important anticancer, anti-inflammatory and healing properties have been widely described. However, studies are still needed to experimentally relate these reported activities to specific classes of compounds. For this, it is important to fractionate extracts in order to guide the purification and identification of new compounds for the development of new drugs.
Tests were performed mostly in vitro and in a smaller number in vivo using rats and mice. However, studies in animal models are still quite limited and need to be further explored to enable future clinical trials. It is necessary to understand the mechanisms of action of these natural products for related activities and submit them to toxicity tests in order to obtain information about their possible side effects, generating a more robust report to verify the feasibility of clinical trials.