The Genus Cynometra: A Review of Ethnomedicine, Chemical, and Biological Data

Cynometra L. is a Fabaceae genus that is widely distributed throughout the tropics, consisting of tropical forest trees with ecological and economic importance since they are used as food and herbal medicines by the populations of their natural habitats. Our goal is to provide a review of the research data concerning the potential of this botanical genus as a source of herbal medicines and secondary metabolites that are useful for human health. To that end, scientific databases, including PubMed, Science Direct, ISI Web of Science, Scopus, and Google Scholar, were searched using the following terms: Cynometra, medicine, chemical, biological activity, toxicity, and “AND” as the Boolean connector. Eleven Cynometra species (9.7%) were reported to be used in traditional medicine to treat different ailments. A total of 185 secondary metabolites of various chemical classes, mainly flavonoids and terpenoids, were identified in eight Cynometra species (7.1%). Vitexin was the only flavonoid identified as bioactive in the sequence of bioguided studies on this botanical genus. Ten species (8.8%) were submitted to in vitro and in vivo biological activity assays. The main evaluated activities were in vitro antioxidant, antimicrobial, cytotoxic, and in vivo anti-inflammatory activities, but no human clinical trials or safety data about this genus were found. Cynometra cauliflora and Cynometra ramiflora were the most studied species. The present work confirms the use of Cynometra species as a source of medicinal plants. However, more experimental studies must be conducted to better understand this botanical genus’s usefulness as a source of raw materials for pharmaceutical use.


Introduction
The genus Cynometra L. is a species-rich genera in the most significant tropical family Fabaceae (Leguminosae) and subfamily Detarioideae, described for the first time in 1741 by Linnaeus and included in the first edition of Species Plantarum (published in 1753) [1]. This botanical genus has a wide distribution and high diversity. It is classified using regional groupings of species (the Neotropics, Tropical Africa, Madagascar, the Comoros Islands, and the Indo-Pacific groups) [1][2][3]. According to phylogenetic studies, the Cynometra genus is polyphyletic [4][5][6][7][8].
Cynometra species are generally recognized as used in traditional medicine in the countries where they exist as part of the spontaneous flora. Traditional practitioners usually prepare medicine from different plant parts and by different modes of preparation to treat various ailments. However, it should be noted that only a little information was available related to the concrete use for the treatment of different pathological signals or symptoms and their chemical, pharmacological, and toxicological properties. So, to gain and give a clear idea about a genus, it is very important to collect, arrange, and review all necessary information concerning medicinal importance of the genus.
In the present work, a revision of the ethnomedical, chemical, pharmacological, and toxicological data on the genus Cynometra is presented and discussed to better characterize the potential of this botanical genus as a source of medicinal plants and traditional herbal medicines, and as a source of natural products that could be useful for the development of new drugs.  Cynometra species are generally recognized as used in traditional medicine in the countries where they exist as part of the spontaneous flora. Traditional practitioners usually prepare medicine from different plant parts and by different modes of preparation to treat various ailments. However, it should be noted that only a little information was available related to the concrete use for the treatment of different pathological signals or symptoms and their chemical, pharmacological, and toxicological properties. So, to gain and give a clear idea about a genus, it is very important to collect, arrange, and review all necessary information concerning medicinal importance of the genus.
In the present work, a revision of the ethnomedical, chemical, pharmacological, and toxicological data on the genus Cynometra is presented and discussed to better characterize the potential of this botanical genus as a source of medicinal plants and traditional herbal medicines, and as a source of natural products that could be useful for the development of new drugs. the following reasons: repeated results, no relation to medicinal issues, and inclusion of irrelevant or incomplete information. Finally, a total of 85 scientific publications were considered eligible to be included in this review. The inclusion criteria were publications related to Cynometra genus; abstracts or full texts in English; and studies on Cynometra species concerning medicinal importance. In Figure 3, the number of selected scientific publications according to the respective publication years is presented.

Selection of the Information
Details of data collection and choice are given in Figure 2. The initial titles and abstract search yielded 8309 results. After excluding duplicates, 4980 scientific publications were reviewed for eligibility. Of those, 4895 scientific publications were excluded for the following reasons: repeated results, no relation to medicinal issues, and inclusion of irrelevant or incomplete information. Finally, a total of 85 scientific publications were considered eligible to be included in this review. The inclusion criteria were publications related to Cynometra genus; abstracts or full texts in English; and studies on Cynometra species concerning medicinal importance. In Figure 3, the number of selected scientific publications according to the respective publication years is presented.

Ethnomedicinal Data
Eleven Cynometra species, i.e., C. brachyrrhachis, C. capuronii, C. cauliflora, C. hankei, C. iripa, C. manii, C. megalophylla, C. ramiflora, C. spruceana, C. vogelii, and C. webberi, have been reported for their ethnomedicinal uses ( Table 2). The leaf, fruit, seed, stem, bark, resin, and root of these species are traditionally used for the treatment of digestive disorders, respiratory problems, skin, and inflammatory diseases. For example, the decoction of the C. cauliflora leaf is used to treat diabetes and hyperlipidemia [15]; however, in Indonesia, the fruit of this species is used as food, and the leaf is used as medicine for the treatment of diarrhea [16].

Ethnomedicinal Data
Eleven Cynometra species, i.e., C. brachyrrhachis, C. capuronii, C. cauliflora, C. hankei, C. iripa, C. manii, C. megalophylla, C. ramiflora, C. spruceana, C. vogelii, and C. webberi, have been reported for their ethnomedicinal uses ( Table 2). The leaf, fruit, seed, stem, bark, resin, and root of these species are traditionally used for the treatment of digestive disorders, respiratory problems, skin, and inflammatory diseases. For example, the decoction of the C. cauliflora leaf is used to treat diabetes and hyperlipidemia [15]; however, in Indonesia, the fruit of this species is used as food, and the leaf is used as medicine for the treatment of diarrhea [16].
The leaf was found to be the most used Cynometra plant part for medicinal purposes. The decoction and powder are mainly used in the preparation of herbal medicine.
According to our results, among the total number of 113 Cynometra species, only 9.7% have been recorded for their traditional uses ( Table 2).   C. iripa leaf, seed, stem India wound healing [22] leaf India ulcers decoction [23] seed oil India cholera not available [24] C. manii stem Nigeria to suppress swelling in the cheeks [25] bark Nigeria cancer [26] C. megalophylla seed Nigeria fibroid treatment [27] leaf Benin stomach infections [28] C. ramiflora leaf, root India purgative, skin diseases [29] whole plant Bangladesh skin diseases powder [30] C. spruceana resin Brazil weakness of the lungs, tuberculosis, chronic cough not available [31] C. vogelii stem Nigeria oral hygiene [32] C. webberi root Tanzania skin diseases [17] Plants 2022, 11, 3504 6 of 14 The leaf was found to be the most used Cynometra plant part for medicinal purposes. The decoction and powder are mainly used in the preparation of herbal medicine.
According to our results, among the total number of 113 Cynometra species, only 9.7% have been recorded for their traditional uses (Table 2).

Chemical Compounds
In Table 3, the main compounds isolated and identified from the studied chemicals of eight Cynometra species (7.1%) are presented. Flavonoids and terpenoids are the major chemical classes reported on this botanical genus beside fatty acids, alkaloids, esters, and other phenol derivatives. C. cauliflora was the most studied plant species.
The presence of tannins, flavonoids, and terpenoids was reported in the aqueous extracts of stem, bark, and leaf [19], as well as in a methanolic extract of C. cauliflora leaf [33]. Cardiac glycosides were present in the different parts of the plant, except on the stem [19]. Ethanol extract of C. ramiflora leaf was revealed to contain alkaloids, phenolic compounds, and terpenoids (saponins and steroids) [34,35]. The existence of tannins was found in the ethanol, hexane, and dichloromethane extracts of the stem and root of C. vogelli [32]. Preliminary phytochemical screening of an ethanolic extract of C. malaccensis leaf, twig, and stem bark showed the presence of flavonoids, terpenoids, and high content of tannins. [36]. The presence of alkaloids in the leaf and stem [37] and different type of fatty acids in leaf and seed [38] have been reported in C. iripa. Basak et al. (1996) also noted the presence of chlorophyll, carotenoids, proteins, polyphenols, and tannins in the seed of this species [39]. The existence of phenol derivatives, including gallotannins, leucoanthocyanins and anthraquinones, and of saponins and steroids were reported from C. capuronii leaf [18].
At least 14 fatty acids were found in the oil of C. iripa seed, while 10 fatty acids were in the leaf oil. Linoleic acid (34.2%) was prominent in seed oil, and palmitic acid (33.5 %) was prominent in leaf oil [38].
The presence of imidazole alkaloids that are characteristic of this botanical genus were noticed in C. anata (leaf) [44], C. hankei (stem bark and seed) [45], and C. lujae (not indicated) [44]. In Figure 4, some examples of imidazole alkaloids are given.
Some chemical studies related to the quantification of representative secondary metabolites classes were also performed. The total phenolic content (TPC) of a young leaf of C. cauliflora was found to be 1831.47 ± 1.03 mg GAE (gallic acid equivalent)/g, and the total flavonoid content (TFC) was found to be 33.63 ± 0.25 mg CE (catechin equivalent)/g [19]. However, the ethanol extract of the leaf and fruit of C. cauliflora was reported to have TPC 344.17 ± 10.80 and TPC 122.04 ± 3.17 mg GAE/g plant extract [46,47]. The methanol and aqueous extracts of C. cauliflora fruit showed a TPC of 1868.94 ± 11.68 (mg GAE/100 g edible portion) and of 1.30 ± 0.10 (mg GAE/g dry weight), respectively, [48,49], whereas in another study, the aqueous extract of this species showed TPC 4.6 ± 0.06 mg GAE/g dry weight. The TMAC (total monomeric anthocyanin content) and vitamin C content of C. cauliflora fruit aqueous extract were 8.66 ± 1.68 and 21.8 ± 0.33, respectively [50]. In a recent study, Abeysuriya et al. (2020) reported low content of vitamin C (37.9 ± 1.8 mg/100 g Plants 2022, 11, 3504 7 of 14 fresh weight) from seedless fruit extract of C. cauliflora (extraction solvent: 3% (w/v) meta-phosphoric acid and 8% (v/v) glacial acetic acid) and medium TPC (428.5 ± 1.3 mg GAE/100 g fresh weight) and TFC (26.1 ± 1.0 mg QE (quercetin equivalent)/100 g fresh weight) from MeOH (methanol) extract of the same [51].

Biological Studies
Results of the in vitro and in vivo biological activity tests made on the Cynometra genus are summarized in Table S1 (please consult our supplementary data, all references are orderly according to its occurrence on this table). A total of ten species (8.8%), namely, C. bauhiniifolia, C. brachyrrhachis, C. cauliflora, C. cloiselii, C. iripa, C. madagascariensis, C. ramiflora, C. spruceana, C. travancorica, and C. vogelii, were studied. Among them, C. cauliflora and C. ramiflora were found to be the most important species concerning biological activities. Methanol and ethanol were mostly used as extraction solvents, and leaf and fruit were the most important plant parts to show different biological activities.

Biological Studies
Results of the in vitro and in vivo biological activity tests made on the Cynometra genus are summarized in Table S1 (please consult our supplementary data, all references are orderly according to its occurrence on this table). A total of ten species (8.8%), namely, C. bauhiniifolia, C. brachyrrhachis, C. cauliflora, C. cloiselii, C. iripa, C. madagascariensis, C. ramiflora, C. spruceana, C. travancorica, and C. vogelii, were studied. Among them, C. cauliflora and C. ramiflora were found to be the most important species concerning biological activities. Methanol and ethanol were mostly used as extraction solvents, and leaf and fruit were the most important plant parts to show different biological activities.
The leaf and fruit of C. cauliflora were the most biologically tested plant parts of this species: A methanol leaf extract showed significant antioxidant [15,60,62,63]; antibacterial (against Staphylococcus aureus, Escherichia coli, Porphyromonas gingivalis, and methicillinresistant Staphylococcus aureus [33,62,67]); anti-viral (against herpes simplex virus type 1) [71]; anti-diabetic; antidiarrheal (in vivo) [63]; and cytotoxic potentiality against brine shrimp (Artemia salina) and Vero cells [71,72]. An ethanol leaf extract showed anti-inflammatory activity by inhibiting the activities of arachidonate-5-lipoxygenase and hyaluronidase [64]. In addition, the same extract exhibited strong antioxidant and high inhibitory alpha-glucosidase activities [46], as well as moderate cytotoxic activity (against HeLa cancer cells) [74]. Moreover, this extract and vitexin, a flavonoid isolated from this medicinal plant, were observed to be involved in its in vivo anti-obesity and lipid-lowering activities [69], and an aqueous leaf extract showed antioxidant and potent anti-diabetic activity in vivo [65,73].
A methanol extract of the fruit exhibited cytotoxic activity (against human promyelocytic leukemia HL-60 and normal mouse fibroblast NIH/3T3 cell lines) and low antioxidant activities [46,59]. A fruit's hexane, chloroform, ethyl acetate, ethanol, methanol, and aqueous extracts showed antifungal activity against four species of yeasts (Candida albicans, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans), and two species of filamentous fungi (Aspergillus fumigatus and Trichophyton interdigitale) [66]. In two other studies, the fruit aqueous extract showed significant antioxidant activity [49,50]. In contrast, the methanol extract of the same plant part showed a low antioxidant activity [48].
Concerning C. cauliflora, the stem and the essential oils were also studied: The stem ethyl acetate and methanol extracts showed, strong antioxidant and anticholinesterase activities (>80% inhibition), respectively [53,68]. The leaf and fruit of C. cauliflora were the most biologically tested plant parts of this species: A methanol leaf extract showed significant antioxidant [15,60,62,63]; antibacterial (against Staphylococcus aureus, Escherichia coli, Porphyromonas gingivalis, and methicillinresistant Staphylococcus aureus [33,62,67]); anti-viral (against herpes simplex virus type 1) [71]; anti-diabetic; antidiarrheal (in vivo) [63]; and cytotoxic potentiality against brine shrimp (Artemia salina) and Vero cells [71,72]. An ethanol leaf extract showed anti-inflammatory activity by inhibiting the activities of arachidonate-5-lipoxygenase and hyaluronidase [64]. In addition, the same extract exhibited strong antioxidant and high inhibitory alphaglucosidase activities [46], as well as moderate cytotoxic activity (against HeLa cancer cells) [74]. Moreover, this extract and vitexin, a flavonoid isolated from this medicinal plant, were observed to be involved in its in vivo anti-obesity and lipid-lowering activities [69], and an aqueous leaf extract showed antioxidant and potent anti-diabetic activity in vivo [65,73].
A methanol extract of the fruit exhibited cytotoxic activity (against human promyelocytic leukemia HL-60 and normal mouse fibroblast NIH/3T3 cell lines) and low antioxidant activities [46,59]. A fruit's hexane, chloroform, ethyl acetate, ethanol, methanol, and aqueous extracts showed antifungal activity against four species of yeasts (Candida albicans, Candida parapsilosis, Candida krusei, and Cryptococcus neoformans), and two species of filamentous fungi (Aspergillus fumigatus and Trichophyton interdigitale) [66]. In two other studies, the fruit aqueous extract showed significant antioxidant activity [49,50]. In contrast, the methanol extract of the same plant part showed a low antioxidant activity [48].
Concerning C. cauliflora, the stem and the essential oils were also studied: The stem ethyl acetate and methanol extracts showed, strong antioxidant and anticholinesterase activities (>80% inhibition), respectively [53,68].
The essential oils obtained from leaves, twigs, and fruits showed antioxidant activity, whereas the observed twig oil was more active than the oil from the other plant parts and showed significant antibacterial and cytotoxic activities (against MCF-7 cells) [40].
C. ramiflora was also one of the main Cynometra species studied, and the leaf was the most used plant part: A methanol extract of this medicinal plant showed significant antihyperglycemic activity [80], low anti-ulcer activity (13.9% inhibition) [35], antioxidant activity [86], and cytotoxic activity (against brine shrimp) [52].

Toxicity
Only one study had been found concerning the toxicity of Cynometra medicinal plants and preparations. In this study, the authors reported that C. ramiflora leaf ethanolic extracts at 1000 and 1500 mg/kg BW (body weight) doses cause in vivo inflammation in the rat kidney [99].
No clinical toxic effects of Cynometra species on humans have been recorded.

Materials and Methods
This review was performed following the criteria described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 2020 (https:// prisma-statement.org/prismastatement/flowdiagram.aspx; accessed on 1 January 2022)).

Search Strategy
The scientific data were collected from PubMed, Science Direct, Web of Science, B-on, and Google Scholar, selecting all the scientific publications published between 1 January 1980 and 30 June 2022, by using keywords Cynometra AND medicine, Cynometra AND chemical compounds, Cynometra AND biological activity, and Cynometra AND toxicity.

Conclusions and Future Perspectives
The results of our work revealed that from the total amount of 113 species of the Cynometra genus, eleven (9.7%) have been reported as used in ethnomedicine, mainly for skin disease treatment. Eight species (7.1%) of this botanical genus were submitted to chemical studies and ten species (8.8%) to biological activity. The main activities evaluated were the antioxidant, antimicrobial, cytotoxic, and anti-inflammatory activities, but safety data on species of this botanical genus were almost inexistent. It has also observed that not all the species cited as used in traditional medicine, such as C. capuronii, C. manii, and C. webberi, were chemically or biologically studied. On the other hand, the leaf, and seed of C. megallophylla were documented as traditional medicines, but only the root was submitted to phytochemical studies, and no biological data have been reported concerning this species.
The genus Cynometra was observed to be a botanical resource of secondary metabolites that can be related to the biological activities and the therapeutical uses described for the medicinal plants integrating it. However, to form a better conclusion about the medicinal value of each of these medicinal plants, more scientific studies concerning their safety and mode of action must be conducted, in addition to studies concerning their metabolomic, botanical, and genetic profiles, which will allow for the establishment of the much-needed quality control criteria for their better use in medicine.
Author Contributions: S.S. and K.H.: Information collection, writing. I.B.M.d.S. and J.R., R.S. and N.I.: Revision of the manuscript. O.S.: Supervision, conceptualization, study design, writing, editing, and revision the manuscript. All authors agree to be accountable for all aspects of work, ensuring integrity and accuracy. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Foundation for Science and Technology (FCT, Portugal) through national funds to iMed.ULisboa (UIDP/04138/2020).

Conflicts of Interest:
The authors confirm that they have no conflict of interest regarding the content of this article.