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A REVIEW OF ETHNOMEDICINAL USES, PHYTOCHEMICAL AND PHARMACOLOGICAL PROPERTIES OF CAPENSE ()

Alfred Maroyi Department of Botany, University of Fort Hare, Private Bag X1314, Alice 5700, ; Phone/Fax: 0027406022322; E-mail: [email protected]

ABSTRACT (L. f.) Thunb. is a medium to large tree widely used as traditional medicine in tropical Africa. This study is aimed at evaluating the ethnomedicinal uses, phytochemical and pharmacological properties of C. capense. Results of the current study are based on data derived from several online databases such as Scopus, Google Scholar, PubMed and Science Direct, and pre-electronic sources such as scientific publications, books, dissertations, book chapters and journal articles. This study revealed that the bark, fruit, leaf, seed and stem bark infusion and/or decoction of C. capense are mainly used as dermatological agents, insecticide and protective charm, and traditional medicines for skin infections, toothache, cough, fever and stomach problems. Phytochemical compounds identified from the species include alkaloids, coumarins, fatty acids, limonoids, methyl esters and terpenoids. Pharmacological research revealed that C. capense extracts and compounds isolated from the species have antibacterial, antimycobacterial, antifungal, antiprotozoal, antioxidant, antiproliferative, insecticidal, larvicidal and cytotoxicity activities. Calodendrum capense should be subjected to detailed phytochemical, pharmacological and toxicological evaluations aimed at correlating its medicinal uses with its phytochemistry and pharmacological properties. Keywords: Calodendrum capense, indigenous pharmacopeia, Rutaceae, traditional medicine

1. Introduction Calodendrum capense (L. f.) Thunb. (Fig. 1) is a medium to large deciduous to evergreen tree belonging to the Rutaceae or citrus family. The genus Calodendrum Thunb. comprises of two tree species, C. capense and C. eickii Engl. Calodendrum eickii is a rare deciduous tree confined to the dry montane forests of the West Usambara Mountains in Tanzania which differs from C. capense in having smaller flowers and larger fruits with long spine-like warts [1]. The genus name Calodendrum is a contraction of two Greek words “kalos” meaning “beautiful” and “dendron” meaning “tree” [2,3]. The specific epithet “capense” means “from the Cape” [4]. The synonyms associated with the name C. capense include Dictamus calodendrum Poir., D. capensis L.f. and Pallassia capensis Christm. [5]. The English common names of C. capense are “cape chestnut” and “wild chestnut” [6,7]. Calodendrum capense has a sharply spreading crown, bare for several months and growing to a height of 25 metres [8,9]. The bark is smooth and grey in colour, the bole sometimes with few lenticels and becoming buttressed with age. The leaves are simple, opposite, broadly elliptic to oval in shape, hairless when mature, aromatic when crushed, with entire and waxy margins [10,11]. The flowers are large and showy, pink to purple in colour and occur in dense, branched axillary and terminal heads [12,13]. The fruit is a large and woody capsule with a knobbly texture. Calodendrum capense has been recorded in Eswatini, Lesotho, Kenya, Malawi, South Africa, Tanzania, Uganda and Zimbabwe [14-17]. Calodendrum capense has been recorded in dry black cotton soils, moist forest soils, sheltered rocky slopes and kloofs in

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evergreen afromontane forest, riverine thicket, higher altitude forests, evergreen fringe forest, forest margins, densely wooded ravines and scrub vegetation at an altitude ranging from 5 m to 2300 m above sea level [8,18-20].

Fig. 1: Calodendrum capense A: branch showing flowers and B: branch showing a fruit (photos: B Wursten)

Calodendrum capense was introduced to Australia, north Africa and several other countries throughout the world as an ornamental , mainly grown for its highly aesthetic, fragrant pink flowers and prolific flower display [20,21]. Calodendrum capense is good for bee forage, serves as shade, hedge and for mulching to enhance soil fertility [22,23]. The kernels of C. capense yield a yellow, bitter, non-drying oil which is traditionally used for making

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cosmetic soap [24,25]. The seed oil of C. capense is popular in tropical Africa where it is used as a skin-care product and skin emollient and the oil has a high potential for use as lubricant and as fuel in diesel engines [26,27]. The bark of C. capense is traded as traditional medicine in the informal herbal medicine markets of the Eastern Cape, Gauteng, KwaZulu- Natal and Mpumalanga provinces in South Africa [28-35]. Similarly, the bark and roots of C. capense are also traded as traditional medicine in informal herbal medicine markets in Malawi [36]. It is therefore, within this context that the current study was undertaken aimed at documenting the ethnomedicinal uses, phytochemical and pharmacological properties of C. capense.

2. Materials and methods Results of the current study are based on literature search on the chemical properties, biological activities and ethnomedicinal uses of C. capense using information derived from several internet databases. The databases included Scopus, Google Scholar, PubMed and Science Direct. Other sources of information used included pre-electronic sources such as journal articles, theses, books, book chapters and other scientific articles obtained from the University library. A total of 68 articles published between 1951 and 2020 were used in this study (Fig. 2).

Fig. 2: Flow diagram showing literature search and selection processes

3. Results and discussion 3.1 Medicinal uses of Calodendrum capense Medicinal uses of C. capense have been recorded in Eswatini, Kenya and South Africa (Table 1), representing 37.5% of the countries where the species is indigenous. The leaf, fruit, seed and stem bark infusion and/or decoction of C. capense are mainly used as dermatological agents, insecticide and protective charm, and traditional medicines for skin infections, toothache, cough, fever and stomach problems (Table 1, Fig. 3). Other medicinal applications of C. capense include the use of bark, fruit, leaf, seed and stem bark infusion and/or decoction of the species as emetic and to soften hair, and as traditional medicine to easy childbirth, impotency, sterility and snakebite [37-40].

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Table 1: Medicinal uses of Calodendrum capense

Medicinal use Part used Country Reference Cough and fever Bark decoction taken orally Kenya and South [40,41] Africa Dermatological agents (cosmetic, moisturizer, Bark infusion applied topically South Africa [25,39,42-50] skin lightener and treatment) Easy childbirth Bark infusion taken orally Eswatini [37] Emetic Stem bark decoction taken orally Kenya [38] Impotency and sterility Bark infusion taken orally South Africa [40] Insecticide Leaf infusion applied Kenya and South [25,47,51,52] Africa Protective charm (good luck, hunting and Bark and seeds South Africa [2,42,46] love) Skin infections (pimples and rash) Bark and fruit infusion applied topically South Africa [39,44] Snakebite Bark infusion applied topically South Africa [40] Soften hair Fruit infusion applied topically South Africa [39] Stomach problems Stem bark decoction or infusion taken Kenya and South [38,40] orally Africa Toothache Leaf and fruit infusion applied South Africa [39,40]

Insecticide Stomach problems Cough and fever Dermatological agents Protective charm Toothache Skin infections

0 2 4 6 8 10 12

Literature records No. of countries

Fig. 3: Medicinal applications of Calodendrum capense derived from literature records

3.2 Nutritional and phytochemical composition of Calodendrum capense Researchers such as Munavu [53], Wirminghaus et al. [54], Nawiri et al. [55] and Wilson and Downs [56] investigated the nutritional properties of C. capense fruits and seed kernel oil (Table 2). The fruits and seed kernel oil of C. capense could be a source of health promoting nutrients such as copper, lipids, magnesium, manganese, proteins and fatty acids [53-56]. Similarly, the fruit pericarp, leaves, root bark, seeds, seed kernel oil and stem bark yielded alkaloids, coumarins, limonoids, methyl esters and triterpenoids [57-63]. Some of these phytochemical compounds identified from C. capense could be responsible for the biological properties associated with the species.

Table 2: Phytochemical composition of Calodendrum capense

Nutritional or phytochemical compound Value Plant part Reference Nutritional components Copper (μg/g) 3.3 – 5.7 Seed oil [55] Lipids (%) 37.4 Fruits [54,56] Magnesium (μg/g) 94.7 – 138.7 Seed oil [55] Manganese (μg/g) 2.6 – 4.3 Seed oil [55]

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Protein (%) 14.7 – 37.6 Fruits and seed kernel oil [53,54,56] Zinc (μg/g) 10.8 – 14.2 Seed oil [55] Fatty acids Arachidic (%) 1.0 Seed kernel oil [53] Behenic - Seed kernel oil [53] Linoleic (%) 35.6 Seed kernel oil [53] Linolenic (%) 1.4 Seed kernel oil [53] Myristic - Seed kernel oil [53] Oleic (%) 33.7 Seed kernel oil [53] Palmitic (%) 23.8 Seed kernel oil [53] Stearic (%) 4.5 Seed kernel oil [53] Other phytochemical compounds 5-methoxypsolaren - Fruit pericarp, leaves, seeds and stem bark [60] 7-O-dimethylallyl demethylenedictamnine - Fruit pericarp, leaves, seeds and stem bark [60] Bergapten - Fruits, leaves and stem bark [63] Calodendrolide - Root bark and seeds [57-59] Capensenin - Fruits, leaves and stem bark [63] Confusameline - Fruit pericarp, leaves, seeds and stem bark [60,63] Limonin - Fruit pericarp, leaves, seeds, root and stem bark [58,60,63] Limonin diosphenol - Fruit pericarp, leaves, seeds,root and stem bark [58,60,63] Lupeol - Leaves [61,62] Methyl hexadecanoate (%) 23.6 – 35.6 Seed oil [27] Methyl octadecanoate (%) 2.5 – 4.5 Seed oil [27] Methyl-9(Z)-octadecenoate (%) 24.0 – 33.7 Seed oil [27] Methyl-9(Z),12(Z)-octadecadienoate (%) 35.6 – 36.0 Seed oil [27] Psolaren - Fruits, leaves and stem bark [63]

3.3 Pharmacological properties of Calodendrum capense Pharmacological research revealed that the fruit pericarp, leaves, seeds and stem bark of C. capense and compounds isolated from the species have various biological activities such as antibacterial, antimycobacterial, antifungal, antiprotozoal, antioxidant, antiproliferative, insecticidal, larvicidal and cytotoxicity activities (Table 3).

3.3.1 Antibacterial activities Ing’ahu [60] evaluated the antibacterial activities of hexane, dichloromethane, ethyl acetate and methanol extracts of C. capense fruit pericarp, leaves, seeds and stem bark and the compounds 5-methoxypsolaren, 7-O-dimethylallyl demethylenedictamnine, confusameline, limonin and limonin diosphenol isolated. The above compounds were tested against Staphylococcus aureus, Escherichia coli and Bacillus subtilis using the agar diffusion and two-fold serial dilution methods with chloramphenicol as positive control. The extracts and the compound 7-O-dimethylallyl demethylenedictamnine exhibited activities against Staphylococcus aureus and Bacillus subtilis with inhibition zone ranging from 8.0 mm to 14.0 mm while minimum inhibitory concentrations (MIC) values ranged from 1250.0 μg/ml to 2500.0 μg/ml [60]. Sakong [61] and Sakong et al. [62] evaluated the antibacterial activities of acetone, methanol and hexane extracts of C. capense leaves and the compound lupeol isolated from the species showed antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis using the two- fold serial microdilution method with gentamicin (0.1 mg/ml) as positive control. The extracts exhibited activities against tested pathogens with MIC values ranging from 0.2 mg/ml to 0.6 mg/ml while the MIC values exhibited by the compound ranged from 9.0 μg/ml to 75.0 μg/ml [61,62]. Khumalo [46] evaluated the antibacterial activities of dichloromethane and methanol extracts of C. capense bark against Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis using the micro-titre plate technique with ciprofloxacin as positive control. The extracts exhibited activities with MIC values ranging from 2.7 mg/ml to 5.3 mg/ml in comparison to MIC values of 0.02 μg/ml to 0.07 μg/ml

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exhibited by the positive control [46]. Okwemba et al. [63] evaluated the antibacterial activities of hexane, ethyl acetate, dichloromethane and methanol extracts of C. capense fruit pericarp, leaves and stem bark and the compound capensenin isolated from the species was active against Staphylococcus aureus, Escherichia coli and Bacillus subtilis using the agar diffusion and serial dilution methods with chloramphenicol as positive control. The extracts and the compound capensenin exhibited weak activities against Staphylococcus aureus and Bacillus subtilis with inhibition zone ranging from 8.8 mm to 14.0 mm and MIC values ranging from 1200.0 μg/ml to 2500.0 μg/ml [63]. These findings could be used to corroborate traditional uses of C. capense extracts as traditional medicines for cough, fever, stomach problems and toothache [38-41].

Table 3: Summary of pharmacological activities of the extracts from different parts of Calodendrum capense

Activity Extract Plant part Model Effect Reference tested Antibacterial Dichloromethane Leaves Agar diffusion Exhibited activities against Bacillus subtilis and [60] Staphylococcus aureus with inhibition zone of 10.0 mm and 8.0 mm, respectively Ethyl acetate Fruit Agar diffusion Exhibited activities against Staphylococcus aureus with pericarp inhibition zone of 9.0 mm Ethyl acetate Leaves Agar diffusion Exhibited activities against Bacillus subtilis and Staphylococcus aureus with inhibition zone of 12.0 mm and 8.0 mm, respectively Ethyl acetate Stem bark Agar diffusion Exhibited activities against Staphylococcus aureus with inhibition zone of 10.0 mm Hexane Leaves Agar diffusion Exhibited activities against Bacillus subtilis and Staphylococcus aureus with inhibition zone of 11.0 mm and 12.0 mm, respectively Hexane Stem bark Agar diffusion Exhibited activities against Bacillus subtilis and Staphylococcus aureus with inhibition zone of 10.0 mm and 14.0 mm, respectively Methanol Leaves Agar diffusion Exhibited activities against Bacillus subtilis with inhibition zone of 9.0 mm Dichloromethane Fruit Agar diffusion Exhibited activities against Bacillus subtilis with inhibition [63] pericarp zone of 8.8 mm Ethyl acetate Fruit Agar diffusion Exhibited activities against Bacillus subtilis with inhibition pericarp zone of 12.7 mm Hexane Fruit Agar diffusion Exhibited activities against Bacillus subtilis with inhibition pericarp zone of 11.0 mm Methanol Fruit Agar diffusion Exhibited activities against Bacillus subtilis with inhibition pericarp zone of 12.3 mm Dichloromethane Leaves Agar diffusion Exhibited activities against Bacillus subtilis with inhibition zone of 10.3 mm Ethyl acetate Leaves Agar diffusion Exhibited activities against Bacillus subtilis with inhibition zone of 11.7 mm Hexane Leaves Agar diffusion Exhibited activities against Bacillus subtilis and Staphylococcus aureus with inhibition zone of 11.3 mm and 10.0, respectively Methanol Leaves Agar diffusion Exhibited activities against Bacillus subtilis with inhibition zone of 9.0 Ethyl acetate Stem bark Agar diffusion Exhibited activities against Staphylococcus aureus with inhibition zone of 10.0 mm Hexane Stem bark Agar diffusion Exhibited activities against Staphylococcus aureus with inhibition zone of 14.0 mm Dichloromethane Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of [60] 2500.0 μg/ml Ethyl acetate Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of 2500.0 μg/ml Ethyl acetate Stem bark Microdilution Exhibited activities against Staphylococcus aureus with MIC value of 1250.0 μg/ml Hexane Leaves Microdilution Exhibited activities against Bacillus subtilis and Staphylococcus aureus with MIC value of 1250.0 μg/ml Hexane Stem bark Microdilution Exhibited activities against Staphylococcus aureus with MIC value of 2500.0 μg/ml Methanol Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of 2500.0 μg/ml

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Acetone Leaves Microdilution Exhibited activities against Escherichia coli, Pseudomonas [61,62] aeruginosa and Staphylococcus aureus with MIC value of 0.2 mg/ml and Enterococcus faecalis (0.3 mg/ml) Hexane Leaves Microdilution Exhibited activities against Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis with MIC value of 0.6 mg/ml and Staphylococcus aureus (0.2 mg/ml) Methanol Leaves Microdilution Exhibited activities against Escherichia coli and Pseudomonas aeruginosa with MIC value of 0.2 mg/ml, Staphylococcus aureus and Enterococcus faecalis (0.3 mg/ml) Dichloromethane Bark Microdilution Exhibited activities against Pseudomonas aeruginosa with [46] MIC value of 2.7 mg/ml, Staphylococcus aureus (5.3 mg/ml) and Staphylococcus epidermidis (4.0 mg/ml) Methanol Bark Microdilution Exhibited activities against Pseudomonas aeruginosa and Staphylococcus epidermidis with MIC value of 4.0 mg/ml and Staphylococcus aureus (5.3 mg/ml) Dichloromethane Fruit Microdilution Exhibited activities against Bacillus subtilis with MIC value of [63] pericarp 2500.0 μg/ml Ethyl acetate Fruit Microdilution Exhibited activities against Bacillus subtilis with MIC value of pericarp 1250.0 μg/ml Hexane Fruit Microdilution Exhibited activities against Bacillus subtilis with MIC value of pericarp 1250.0 μg/ml Methanol Fruit Microdilution Exhibited activities against Bacillus subtilis with MIC value of pericarp 2500.0 μg/ml Dichloromethane Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of 2500.0 μg/ml Ethyl acetate Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of 2500.0 μg/ml Hexane Leaves Microdilution Exhibited activities against Bacillus subtilis and Staphylococcus aureus with MIC value of 1250.0 μg/ml Methanol Leaves Microdilution Exhibited activities against Bacillus subtilis with MIC value of 2500.0 μg/ml Ethyl acetate Stem bark Microdilution Exhibited activities against Staphylococcus aureus with MIC value of 1200.0 μg/ml Hexane Stem bark Microdilution Exhibited activities against Staphylococcus aureus with MIC value of 2500.0 μg/ml Antimycobact Acetone Leaves Microdilution Exhibited activities against Mycobacterium smegmatis and [61,62] erial Mycobacterium bovis with MIC values of 0.2 mg/ml and 0.3 mg/ml, respectively Hexane Leaves Microdilution Exhibited activities against Mycobacterium smegmatis and Mycobacterium bovis with MIC values of 0.04 mg/ml and 1.3 mg/ml, respectively Methanol Leaves Microdilution Exhibited activities against Mycobacterium smegmatis and Mycobacterium bovis with MIC values of 0.3 mg/ml and 0.2 mg/ml, respectively Antifungal Ethyl acetate Leaves Agar diffusion Exhibited activities against Penicillium citrinium with [60] inhibition zone of 20.0 mm Hexane Fruit Agar diffusion Exhibited activities Penicillium citrinium with inhibition zone pericarp of 13.0 mm Methanol Leaves Agar diffusion Exhibited activities against Penicillium citrinium with inhibition zone of 11.0 mm Hexane Fruit Agar diffusion Exhibited activities against Penicillium citrinium with [63] pericarp inhibition zone of 12.7 mm Ethyl acetate Leaves Agar diffusion Exhibited activities against Penicillium citrinium with inhibition zone of 20.0 mm Methanol Leaves Agar diffusion Exhibited activities against Penicillium citrinium with inhibition zone of 11.0 mm Ethyl acetate Leaves Microdilution Exhibited activities against Penicillium citrinium with MIC [60] value of 1250.0 μg/ml Hexane Fruit Microdilution Exhibited activities Penicillium citrinium with MIC value of pericarp 2500.0 μg/ml Methanol Leaves Microdilution Exhibited activities against Penicillium citrinium with MIC value of 2500.0 μg/ml Hexane Fruit Microdilution Exhibited activities against Penicillium citrinium with MIC [63] pericarp value of 2500.0 μg/ml Ethyl acetate Leaves Microdilution Exhibited activities against Penicillium citrinium with MIC value of 1250.0 μg/ml Methanol Leaves Microdilution Exhibited activities against Penicillium citrinium with MIC value of 2500.0 μg/ml Acetone Leaves Microdilution Exhibited activities against Candida albicans and [61,62] Cryptococcus neoformans with MIC value of 0.3 mg/ml and Aspergillus fumigatus (0.6 mg/ml) Hexane Leaves Microdilution Exhibited activities against Candida albicans with MIC value of 2.5 mg/ml, Cryptococcus neoformans (0.3 mg/ml) and

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Aspergillus fumigatus (1.3 mg/ml) Methanol Leaves Microdilution Exhibited activities against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus with MIC value of 0.6 mg/ml Acetone Leaves Microdilution Exhibited activities against Cryptococcus neoformans with [64] MIC value of 0.04 mg/mL Dichloromethane Leaves Microdilution Exhibited activities against Cryptococcus neoformans with MIC value of 0.2 mg/mL Hexane Leaves Microdilution Exhibited activities against Cryptococcus neoformans with MIC value of 0.6 mg/mL Methanol Leaves Microdilution Exhibited activities against Cryptococcus neoformans with MIC value of 0.6 mg/mL Crude Leaves GIBEX Exhibited activities against Saccharomyces cerevisiae [65] screens-to- nature system Crude Root bark GIBEX Exhibited activities against Saccharomyces cerevisiae screens-to- nature system Crude Stem bark GIBEX Exhibited activities against Saccharomyces cerevisiae screens-to- nature system Antioxidant Crude Leaves ABTS assay Exhibited weak activities [65] Crude Root bark ABTS assay Exhibited weak activities Crude Stem bark ABTS assay Exhibited weak activities Antiproliferat Hexane Fruit Colorimetric Exhibited activities against Vero E-199 cells with IC50 value [63] ive pericarp MTT assay of 81.5 μg/ml Antiprotozoal Crude Leaves Protozoal Exhibited activities against Bodo caudatus [65] lethality assay Crude Root bark Protozoal Exhibited activities against Bodo caudatus lethality assay Crude Stem bark Protozoal Exhibited activities against Bodo caudatus lethality assay Insecticidal Crude Seed Insect Exhibited activities against Protesphanus truncatus with LT50 [51,68] powder mortality varying between 8 days to 14 days assay Crude Seed Insect Exhibited activities by causing adult mortalities of 78.0% of [52] powder mortality Sitophilus zeamais after an exposure period of 28 days assay Crude Seed Insect Exhibited activities by causing adult mortalities of 78.0% of powder mortality Protesphanus truncatus after an exposure period of 28 days assay Larvicidal Crude Root bark Insect Exhibited activities against mosquito 2nd instar larvae of Aedes [51,58] mortality aegypti with LC50 value of 29.2 ppm assay Cytotoxicity Hexane Fruit Colorimetric Exhibited activities against Vero cells-99 with IC50 value of [60] pericarp MTT assay 81.5 μg/ml Hexane Fruit Colorimetric Exhibited activities against Vero cells-E6 with IC50 value of pericarp MTT assay 85.8 μg/ml Crude Leaves Colorimetric Exhibited activities against human liver (C3A) cells with [61,62] MTT assay LC50 value of 83.1 μg/ml

3.3.2 Antimycobacterial activities Sakong [61] and Sakong et al. [62] evaluated the antimycobacterial activities of acetone, methanol and hexane extracts of C. capense leaves and the compound lupeol isolated from the species was active against Mycobacterium smegmatis and Mycobacterium bovis using the two-fold serial microdilution method with gentamicin (0.1 mg/ml) as positive control. The extracts exhibited activities against the tested pathogens with MIC values ranging from 0.04 mg/ml to 1.3 mg/ml while the MIC values exhibited by the compound ranged from 15.0 μg/ml to 31.0 μg/ml [61,62].

3.3.3 Antifungal activities Mokoka et al. [64] evaluated the antifungal activities of hexane, dichloromethane, acetone and methanol leaf extracts of C. capense against Cryptococcus neoformans using the two- fold serial dilution microplate and microdilution methods. The extracts exhibited activities against the tested pathogen with MIC values ranging from 0.02 mg/mL to 0.6 mg/mL and

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total activity ranging from 15.0 mL/g to 1583.0 mL/g [64]. Ing’ahu [60] evaluated the antifungal activities of hexane, dichloromethane, ethyl acetate and methanol extracts of C. capense fruit pericarp, leaves, seeds and stem bark against Candida albicans, Aspergillus niger, Trichophyton mentagrophytes and Penicillium citrinium using the agar diffusion and two-fold serial dilution methods with fluconazole as positive control. The extracts exhibited activities against Penicillium citrinium with inhibition zone ranging from 11.0 mm to 20.0 mm in comparison to inhibition zone of 32.0 mm exhibited by the positive control while MIC values ranged from 1250.0 μg/ml to 2500.0 μg/ml [60]. Sakong [61] and Sakong et al. [62] evaluated the antifungal activities of acetone, methanol and hexane extracts of C. capense leaves and the compound lupeol isolated from the species was active against Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus using the two-fold serial microdilution method with amphotericin B as positive control. The extracts and the compound exhibited activities against tested pathogens with MIC values ranging from 0.02 mg/ml to 2.5 mg/ml with total activity ranging from 24.0 mg/ml to 612.9 mg/ml [61,62]. Okwemba et al. [63] evaluated the antifungal activities of hexane, ethyl acetate, dichloromethane and methanol extracts of C. capense fruit pericarp, leaves and stem bark and the compound capensenin isolated from the species was active against Candida albicans, Trichophyton mentagrophytes, Penicillium citrinium and Aspergillus niger using the agar diffusion and serial dilution methods with fluconazole as positive control. The hexane, ethyl acetate and methanol extracts of fruit pericarp and leaves exhibited activities against Penicillium citrinium with inhibition zone ranging from 11.0 mm to 20.0 mm and MIC values ranging from 1250.0 μg/ml to 2500.0 μg/ml [63]. Omosa et al. [65] evaluated the antifungal activities of the crude extracts of C. capense leaves, root bark and stem bark using the GIBEX screens-to-nature (STN) system against Saccharomyces cerevisiae. The extracts exhibited weak against the tested pathogen [65]. Exhibition of antifungal activities demonstrated by C. capense extracts and the compound isolated from the species is significant since the species is widely used as dermatological agent, particularly as cosmetic, moisturizer and skin lightener treatment in South Africa [25,39,42-50]. Research by Afolayan et al. [39] and Philander [44] revealed that C. capense extracts are used against skin infections such as pimples and rash, and this usage could be attributed to antifungal properties exhibited by the extracts of the species.

3.3.4 Antiprotozoal activities Omosa et al. [65] evaluated the antiprotozoal activities of crude extracts of C. capense leaves, root bark and stem bark against Bodo caudatus using the protozoal lethality test. The extracts exhibited activities against the tested protozoa [65]. This pharmacological evaluation is of importance in the traditional uses of C. capense and future research focusing on control and management of protozoan diseases in the tropics.

3.3.5 Antioxidant activities Omosa et al. [65] evaluated the antioxidant activities of crude extracts of C. capense stem bark using the 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) ammonium salt (ABTS) free radical scavenging assay. The extracts exhibited weak activities [65]. These antioxidant activities exhibited by the crude extracts of C. capense stem bark are probably due to the presence of triterpenoids [66,67] that have been identified from the species [61,62].

3.3.6 Antiproliferative activities Okwemba et al. [63] evaluated the antiproliferative activities of hexane, ethyl acetate, dichloromethane and methanol extracts of C. capense fruit pericarp, leaves and stem bark and the compound capensenin isolated was active against Vero cells using the 3-(4,5-

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dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) calorimetric assay with podophylotoxin as a positive control. The hexane fruit pericarp extract exhibited activities with half maximal inhibitory concentration (IC50) value of 81.5 μg/mL against IC50 value of 65.1 µg/mL exhibited by the positive control [63].

3.3.7 Insecticidal activities Kirui et al. [51,68] evaluated the insecticidal activities of seed powder of C. capense against larger grain borer Protesphanus truncatus using an adult mortality and knockdown assessment test at 0.1% and 0.2% w/w with actellic super 2.0% dust as a positive control at 0.06% w/w. The extract caused adult mortalities of 70.0% after an exposure period of 28 days with a lethal mean mortality exposure time (LT50) varying between 8 days to 14 days [51,68]. Similarly, Kirui et al. [52] evaluated the insecticidal activities of seed powder of C. capense against Protesphanus truncatus and Sitophilus zeamais using an adult mortality and knockdown assessment test with actellic super 2.0% dust as a positive control. The extract caused adult mortalities of 78.0% and 70.0% after an exposure period of 28 days for Sitophilus zeamais and Protesphanus truncatus, respectively [52]. This finding corroborate the traditional use of C. capense as an insecticide in Kenya and South Africa [25,47,51,52].

3.3.8 Larvicidal activities Kirui et al. [51] and Kiprop et al. [58] evaluated the larvicidal activities of crude extract of C. capense root bark and the compounds calodendrolide, limonin and limonin diosphenol isolated from the root bark and seeds of the species. The compounds were active against mosquito 2nd instar larvae of Aedes aegypti at concentrations of 25.0 ppm, 50.0 ppm, 75.0 ppm and 100.0 ppm. The crude extract and the compounds exhibited activities with the median lethal concentration (LC50) values ranging from 13.1 ppm to 217.1 ppm [51,58]. Kiprop et al. [59] evaluated the larvicidal activities of the compound calodendrolide isolated from the root bark of C. capense against mosquito 2nd instar larvae of Aedes aegypti at concentrations of 25.0 μm, 50.0 μm, 75.0 μm and 100.0 μm. The compound calodendrolide exhibited activities causing 100% mortality with the LC50 value of 13.2 μm [59]. The leaf infusions of C. capense are applied topically in Kenya and South Africa to kill insects and parasites [25,47,51,52].

3.3.9 Cytotoxicity activities Ing’ahu [60] evaluated the cytotoxicity activities of hexane, dichloromethane, ethyl acetate and methanol extracts of C. capense fruit pericarp, leaves, seeds and stem bark against vero cells 199 and E6 using the tetrazolium-based colorimetric (MTT) assay with podophylotoxin as a positive control. The hexane extract from the fruit pericarp was slightly toxic to vero cells 199 and vero cell E6 with IC50 values of 81.5 μg/ml and 85.8 μg/ml, respectively in comparision to IC50 value of 65.1 μg/ml exhibited by the positive control [60]. Sakong [61] and Sakong et al. [62] evaluated cytotoxicity activities of the crude extract of C. capense leaves and the compound lupeol isolated was active against human liver (C3A) cells using the tetrazolium-based colorimetric MTT assay with doxorubicin hydrochloride as a positive control. The extract exhibited low toxicity with LC50 value of 83.1 μg/ml and LC50 value of >200 μg/ml for the compound at the highest concentration tested [61,62].

4. Conclusion The present review summarizes the medicinal uses, phytochemistry and pharmacological properties of C. capense. Detailed studies on the pharmacokinetics, in vivo and clinical research involving both extracts and compounds isolated from the species are required. Therefore, future research should focus on the molecular modes or mechanisms of action,

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pharmacokinetics and physiological pathways for specific extracts of the species including identification of the bioactive compounds of the species and their associated pharmacological activities.

Conflict of interest No conflict of interest is associated with this work.

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