Review of phytochemistry, biological activities and therapeutic potential of Cleistochlamys kirkii

Cleistochlamys kirkii (Benth.) Oliv is a shrub or small tree widely used as a traditional medicine in the east and central Africa. Cleistochlamys kirkii is indigenous to Malawi, Mozambique, Tanzania, Zambia and Zimbabwe. This study is aimed at evaluating the phytochemistry, biological activities and therapeutic potential of C. kirkii. 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 scienti ic publications, books, dissertations, book chapters and journal articles. This study revealed that the leaf and root infusion, maceration and decoction of C. kirkii are mainly used as traditional medicines for haemorrhoid wounds, rheumatism and tuberculosis. Phytochemical compounds identi ied from the species include α,β-unsaturated lactone, acetogenin, benzyl benzoate derivatives, c-benzylated lavanone, heptanolide, an indole alkaloid, phenolics, polyoxygenated cyclohexene and derivatives, sesquiterpene and tetracyclic triterpenes. In vitro studies have con irmed thebiological activities ofC. kirkii crude extracts and compounds isolated from the specieswhich include antibacterial, antifungal, antiplasmodial and cytotoxicity. Documentation of the medicinal uses, phytochemistry and pharmacological properties of C. kirkii is essential as this information provides baseline data required for future research and development of health-promoting and pharmaceutical products. Cleistochlamys kirkii should be subjected to detailed ethnopharmacological and toxicological evaluations aimed at correlating its medicinal uses with its phytochemistry and pharmacological properties.


INTRODUCTION
Cleistochlamys kirkii (Benth.) Oliv is a shrub or small tree belonging to the Annonaceae, commonly known as the custard apple family. Annonaceae is one of the most diverse and primitive plant families consisting of about 108 genera and 2400 species worldwide (Chatrou et al., 2012;Attiq et al., 2017) argued that members of the Annonaceae family are used throughout the world as sources of traditional medicines used against arthritis, gastrointestinal problems, hypertension, in lammation, respiratory infections, rheumatism, skin infections, snake bites, sores and wounds. The extracts and phytochemical compounds isolated from Annonaceae species are characterized by analgesic, anthelmintic, antidiabetic, anti-in lammatory, antimicrobial, antioxidant, antipyretic, antiulcer, antinociceptive, antimalarial, antiprotozoal, antileishmanial, cytotoxicity and hepatoprotective properties (Bhardwaj et al., 2019) (Bruschi et al., 2011) General weakness Leaf and root decoction taken orally (Bruschi et al., 2011) Haemorrhoid wounds Leaf decoction applied topically (Nyandoro et al., 2017;Kincses et al., 2018) Hernia Leaf and root decoction taken orally (Bruschi et al., 2014;Monjane, 2017)
Cleistochlamys kirkii (Figure 1) is a much-branched shrub or small straggling tree, seldom taller than 10 metres (Palgrave and Keith, 2002). The bark of C. kirkii is smooth, tough, pale grey to light brown in colour and laking. The leaves are simple, alternate, narrowly oblong to obovate and thinly textured (Burrows et al., 2018). The leaves are dark to bright shiny green above, blue-green and slightly paler below, apex rounded, often notched with a broadly tapering to the rounded base with entire and waxy margins (Strugnell, 2006). The lowers are axillary, sessile, with a heavy sweet scent, creamy-white with reddish-brown bracts below, appearing when trees are lea less. The fruit is a cluster of leshy oval berries which are purple-black when ripe ( Figure 1). Cleistochlamys kirkii has been recorded in alluvium soils in hot and dry bushveld, thickets and river valleys in Malawi, Mozambique, Tanzania, Zambia and Zimbabwe up to an altitude of 900 m above sea level (Drummond, 1975;Silva et al., 2004). The fruit of C. kirkii is eaten fresh or left to stand in water to make a pleasant fruit drink (Tredgold, 1986;Chikuni, 1996). Cleistochlamys kirkii is an important medicinal plant species in southern Africa (Verzar and Petri, 1987;Bruschi et al., 2011). Thus, this review aims to provide an integrated and detailed appraisal of the existing knowledge on the phytochemistry, biological activities and therapeutic potential of C. kirkii.

Medicinal uses of Cleistochlamys kirkii
The leaf and root infusion, maceration and decoction of C. kirkii are mainly used as traditional medicines for haemorrhoid wounds, rheumatism and tuberculosis (Samwel et al., 2007;Pereira et al., 2016) (Table 1). Other medicinal applications of C. kirkii supported by at least two literature records include the use of leaf and root decoction against hernia, muscular pains, stomach ache and venereal diseases (Bruschi et al., 2011;Monjane, 2017).
Antibacterial activities (Odebode et al., 2004a) evaluated the antibacterial activities of crude dichloromethane extract of C. kirkii stem bark and the compounds cleistenolide and pinocembrin isolated from the stem bark of the species against Pseudomonas phaseolicola and Staphyloccocus aureus using the disc method. The crude extract exhibited activities at all concentrations, while the compounds showed moderate to weak activities at concentrations above 200.0 ppm (Odebode et al., 2004b). Similarly, Odebode et al. (2004a) evaluated the antibacterial activities of crude dichloromethane extract of C. kirkii stem bark and the compounds cleistenolide and pinocembrin isolated from the stem bark of the species against Pseudomonas syringae PV. phaseolicola using the disc method with streptomycin as a positive control. The crude extract and the compounds exhibited activities against the tested pathogen with a diameter of inhibition zones ranging from 5.3 mm to 15.0 mm in comparison to the width of inhibition zone of 17.5 mm exhibited by the positive control (Odebode et al., 2004b;Samwel et al., 2007) evaluated the antibacterial activities of the compounds cleistenolide, cleistodienol, (Z)-(+)-5-(2,3-dihydroxy-propylidene)-5H-furan-2-one, melodorinol, acetyl melodorinol, iso-acetyl melodorinol and benzoyl melodorinol isolated from the fruits, leaves, roots and stems of C. kirkii against Staphylococcus aureus and Bacillus anthracis using the hole plate method with chloramphenicol (10.0 µg/mL) as a positive control. The compounds exhibited activities (Samwel et al., 2007;Pereira et al., 2014Pereira et al., , 2015 evaluated the antibacterial activities of n-hexane, dichloromethane, ethyl acetate and methanol extracts and fractions of C. kirkii root bark and the compounds chamanetin, isochamanetin, dichamanetin, echinulin, cis-solamin, cleistenolide, acetylmelodorinol, polycarpol and benzophenone isolated from the species against Salmonella typhymurium, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis, Bacillus subtilis and Staphylococcus aureus using broth microdilution method with amoxicillin, oxacillin and vancomycin as positive controls. The authors also evaluated the type of interaction of the com-pounds with the β-lactam antibiotics amoxicillin and oxacillin using a chemosensitization assay performed on the checkerboard method against Staphylococcus aureus resistant and susceptible strains. The best results were obtained for apolar and polar extracts with minimum inhibitory concentration (MIC) values of 7.5 µg/mL to 62.µg/mL against Gram-positive strains. The compounds chamanetin, isochamanetin, dichamanetin and cleistenolide exhibited activities against the tested pathogens. The compound polycarpol, in combination with antibiotics, exhibited substantial synergistic activities (Pereira et al., 2014(Pereira et al., , 2016Kincses et al., 2018). evaluated the antibacterial activities of the compounds polycarpol, chamanetin, isochamanetin, dichamanetin and acetylmelodorinol isolated from the root bark of C. kirkii against Staphylococcus aureus, Escherichia coli, Chromobacterium violaceum and Enterobacter cloaceae using the microdilution method. The authors also assessed the combined effects of antibiotics cipro loxacin and tetracycline and the compounds chamanetin and dichamanetin by using the checkerboard microdilution method in Staphylococcus aureus strains. The compounds chamanetin and dichamanetin exhibited activities against Staphylococcus aureus with MIC values ranging from 0.8 µM to 25 µM. The combined effect of the antibiotics and the compounds chamanetin and dichamanetin on Staphylococcus aureus resulted in synergism (Kincses et al., 2018) . (Odebode et al., 2004a) evaluated the antifungal activities of crude dichloromethane extract of C. kirkii stem bark and the compounds cleistenolide and pinocembrin isolated from the stem bark of the species against Fusarium solani, Botryodiploida theobromae, Aspergillus niger and Aspergillus lavus using the disc method with benomyl as a positive control. The crude extract and the compounds exhibited activities against Botryodiploida theobromae, Aspergillus niger and Aspergillus lavus with a diameter of inhibition zones ranging from 10.0% to 48.5% in comparison to the diameter of inhibition zone of 100% exhibited by the positive control (Odebode et al., 2004a). Similarly, (Samwel et al., 2007) evaluated the antifungal activities of the compounds cleistenolide, cleistodienol, (Z)-(+)-5-(2,3dihydroxy-propylidene)-5H-furan-2-one, melodorinol, acetyl melodorinol, iso-acetyl melodorinol and benzoyl melodorinol isolated from the fruits, leaves, roots and stems of C. kirkii against Candida albicans using the disk diffusion method with ketoconazole as a positive control. The compounds exhibited activities against the tested pathogen (Samwel et al., Antiplasmodial activities (Nyandoro et al., 2017) evaluated the antiplasmodial activities of the ethanolic crude extract of C. kirkii leaves. The compounds cleistodienediol, cleistodienol A, cleistodienol B, cleistenechlorohydrin A, cleistenechlorohydrin B, cleistenediol F, cleistenonal, cleistophenolide, ent-subglain C, melodorinol, acetylmelodorinol, tetramethylscutellarein and 2-hydroxybenzaldehyde isolated from the species against the chloroquine-sensitive strain of Plasmodium falciparum 3D7 and Dd2 using an imaging-based assay method. The compounds cleistodienediol, cleistodienol A, cleistodienol B and acetylmelodorinol exhibited activities against both 3D7 and Dd2 with half-maximal inhibitory concentration (IC 50 ) values ranging from 0.2 µM to 40.0 µM (Nyandoro et al., 2017). Similarly, (Nyandoro et al., 2019) evaluated the antiplasmodial activities of ethanolic crude extract of C. kirkii root bark and the compounds cleistonol, chamanetin, isochamanetin, dichamanetin, 7methoxyisochamanetin, pinostrobin, pinocembrin, benzyl benzoate, 2-methoxybenzyl benzoate, guaiol, polycarpol, (E)-acetylmelodorinol and cleistenolide isolated from the species against the chloroquinesensitive strain of Plasmodium falciparum 3D7 using an imaging-based assay method with artesunate as the reference drug. The crude extract gave 72.0% inhibition against the 3D7 strain at 0.01 µg/mL, while the compounds dichamanetin, (E)acetylmelodorinol and cleistenolide exhibited IC 50 values of 9.3 µM, 7.6 µM and 15.2 µM, respectively, against 3D7 (Nyandoro et al., 2019). (Samwel et al., 2007) evaluated the cytotoxicity activities of the compounds cleistodienol, (Z)-(+)-5-(2,3-dihydroxy-propylidene)-5H-furan-2-one, melodorinol, acetyl melodorinol, iso-acetyl melodorinol and benzoyl melodorinol isolated from the fruits, leaves, roots and stems of C. kirkii using the brine shrimp assay. The compounds exhibited activities with half-maximal lethal dose (LD 50 ) value of 0.09 µg/mL (Samwel et al., 2007). Similarly, (Nyandoro et al., 2017) evaluated the cytotoxicity activities of the ethanolic crude extract of C. kirkii leaves. The compounds cleistodienediol, cleistodienol A, cleistodienol B, cleistenechlorohydrin A, cleistenechlorohydrin B, cleistenediol F, cleistenonal, cleistophenolide, ent-subglain C, melodorinol, acetylmelodorinol, tetramethylscutellarein and 2-hydroxybenzaldehyde isolated from the species against HEK-293 cells and MDA-MB-231, triple-negative, aggressive breast cancer cell line. All the compounds exhibited activities with IC 50 values ranging from 0.03 µM to 8.2 µM (Nyandoro et al., 2019). (Nyandoro et al., 2019) also evaluated the cytotoxicity activities of ethanolic crude extract of C. kirkii root bark and the compounds cleistonol, chamanetin, isochamanetin, dichamanetin, 7methoxyisochamanetin, pinostrobin, pinocembrin, benzyl benzoate, 2-methoxybenzyl benzoate, guaiol, polycarpol, (E)-acetylmelodorinol and cleistenolide isolated from the species against the triple-negative aggressive breast cancer cell line MDA-MB-231 using Alamar Blue assay with lupeol as the reference drug. The crude extract exhibited activities with an IC 50 value of 42.0 µg/mL. In contrast, the compounds chamanetin, isochamanetin, dichamanetin, pinocembrin, (E)-acetylmelodorinol and cleistenolide exhibited activities with IC 50 values ranging from 9.6 µM to 30.7 µM (Nyandoro et al., 2019).

CONCLUSIONS
The current scienti ic evidence, as illustrated by biological activities demonstrated by C. kirkii, indicates its potential as traditional medicine. The biological activities exhibited by the extracts and compounds isolated from the species directly or indirectly support a wide range of physiological processes, which offers protection against the growth of undesirable microbes and cytotoxicity properties which could trigger antitumor activities. The present study showed that there are still some research gaps in the phytochemistry, pharmacological and toxicological properties of the species. Therefore, further rigorous research is required aimed at evaluating the phytochemical properties of the different plant parts used as sources of traditional medicines as well as clinical trials and in vivo experiments.

ACKNOWLEDGEMENT
I am grateful to the reviewers who kindly commented on my manuscript.