Introduction

Ehretia amoena Klotzsch (Figure 1) is a shrub or small tree belonging to the Ehretiaceae. Recent molecular and phylogenetic studies based on nuclear (ITS) and plastid loci (rps16, trnL-trnF and trnS-trnG) supported the segregation of the family Ehretiaceae from Boraginaceae sensu lato (Gottschling, Weigend, & Hilger, 2016). The Ehretiaceae family comprise ten genera, that is, Bourreria P. Br., Coldenia L., Cordia L., Cortesia Cav., Ehretia P. Br., Halgania Gaudich., Hoplestigma Pierre, Lepidocordia Ducke, Rochefortia Sw. and Tiquilia Pers. With about 500 species and are pantropical in distribution, with centres of diversity in Central America and the Caribbean, Africa, and East Asia. The genus Ehretia consists of shrubs and trees with approximately 40 species (Gottschling et al., 2016). The plant species belonging to the genus Ehretia have been recorded in the Old and New World tropics with a few species in tropical America and the West Indies, with centres of diversity in tropical Africa and East Asia. Several Ehretia species are widely used as sources of traditional medicines in tropical Africa and these species are listed in the monograph “Plant Resources of Tropical Africa 11(1): Medicinal Plants 1”. Such plant species include E. amoena, E. bakeri Britten, E. cymosa Thonn., E. obtusifolia DC., E. rigida (Thunb.) Druce and E. trachyphylla C.H. Wright. (Shukla & Kaur, 2018) argued that the medicinal uses of Ehretia species could be attributed to alkaloids, benzoquinones, cyanogenetic glycosides, fatty acids, phenolic acids, flavonoids and other phytochemical compounds identified from different species.

The pharmacological properties associated with crude extracts and phytochemical compounds isolated from the species include anti-inflammatory, antiarthritic, antibacterial, antitubercular, antioxidant, antiallergic, antitrypanosomal, antiprotozoal, antidiabetic, cardiotonic activities, as well as anti-snake venom properties.

Ehretia amoena occurs naturally in Eswatini, Kenya, Malawi, Mozambique, Namibia, South Africa, Tanzania, Uganda, Zambia and Zimbabwe (Martins, Brummitt, & Boraginaceae, 1990; Verdcourt, 1991). The genus name Ehretia is in honour of a German botanical artist and entomologist of the 18^th century known as Georg Dionysius Ehret (1708-1770). The species name amoena is a Latin word that means “charming” and “pleasant” in reference to showy and beautiful flowers (see Figure 1). The English common names of E. amoena include “sandpaper-bush” and “sandpaper stamperwood” (Schmidt, Lotter, & McCleland, 2017; Wyk & Wyk, 2013). Synonyms of E. amoena include E. goetzei Gürke, E. mossambicensis Klotzsch, E. stuhlmannii Gürke and Ficus obovata Sim (Retief & Wyk, 2001; Verdcourt, 1991).

Ehretia amoena is a deciduous shrub or small tree with somewhat arching branches and can grow up to five metres in height. Ehretia amoena has been recorded in medium to low altitudes, at the margins of coastal forests, riverine forest, in riparian thickets, bushveld, woodland, termite mounds, along watercourses and in alluvial and sandy soils. The bark of E. amoena is smooth but flaking in older trees, light grey-brown to dark grey in colour. The leaves are simple, alternate and entire, broadly ovate to elliptic in shape, both surfaces with short hairs lying flat against the surface, dark green above and paler dull green below with midrib and lateral veins prominent and net-veining conspicuous. Flowers of E. amoena are white to pale mauve in colour, sweetly scented occurring in large terminal heads. The fruit is a drupe, ovoid to globose in shape, fleshy, hairless, red in colour when ripe.

The fruits of E. amoena are edible but not very tasty, widely used as a snack (Fox, Norwood, & Young, 1982; Welcome & Wyk, 2019). The leaves and young shoots of E. amoena are browsed by game and livestock (Mtengeti & Mhelela, 2006; Peters, O'Brien, & Drummond, 1992). The leaves of E. amoena are sold as traditional medicines in informal herbal medicine markets in Tanzania (Posthouwer et al., 2018; Posthouwer, 2015). It is therefore, within this context that the current study was undertaken aimed at documenting the medicinal uses, phytochemistry and pharmacological properties of E. amoena so as to provide baseline data required in evaluating the therapeutic potential of the species.

Materials and Methods

An extensive literature survey related to E. amoena was conducted using various search engines such as Elsevier, Pubmed, Google Scholar, Springer, Science Direct, Taylor and Francis, and pre-electronic sources such as books, book chapters, scientific journals and other grey literature. The literature search was conducted using keywords such as "Ehretia amoena”, “medicinal uses of Ehretia amoena”, “phytochemicals of Ehretia amoena”, “biological activities of Ehretia amoena”, “ethnobotany

of Ehretia amoena”, and various other synonyms and common names of the plant species.

Result and Discussion

Medicinal uses of Ehretia amoena

The bark, fruit, leaf, root, root bark, stem and stem bark decoction or infusion of E. amoena are mainly used as anthelmintic and traditional medicine for fever, typhoid, sleeping sickness, wounds, menstrual problems, abdominal pains, sexually transmitted infections, skin diseases, vomiting, pain, muscle pain and gastro-intestinal problems (Table 1, Figure 2). Other medicinal applications of E. amoena supported by at least two literature sources include the use of root infusions against convulsions and epilepsy (Chhabra et al., 1987; Moshi et al., 2005) and use of leaf infusions against hypertension (Posthouwer et al., 2018; Posthouwer, 2015).

Phytochemical composition of Ehretia amoena

Researchers such as (Chhabra et al., 1984) and (Räz et al., 1996) identified phytochemical compounds such as chrysosplenetin, chrysosplenol D, emodins, polyose, polyuronoids, saponins, steroids, tannins, terpenoids and volatile oils from the leaves and roots of E. amoena (Table 2).

Some of these phytochemical compounds identified from E. amoena could be responsible for the pharmacological properties associated with the species.

Pharmacological properties of Ehretia amoena

Pharmacological research revealed that aerial parts, leaves, root bark, roots and stem bark of E. amoena and compounds isolated from the species have various biological activities such as antibacterial, antitrypanosomal and cytotoxicity activities.

Antibacterial activities

(Khan & Nkunya, 1990) evaluated the antibacterial activities of crude extracts of E. amoena root bark against Staphylococcus aureus and Escherichia coli using agar diffusion method. The extracts exhibited activities against tested pathogens with a zone of inhibition ranging from 10.0 mm to 25.0 mm (Khan et al., 1990). Preliminary studies evaluating the antibacterial activities of the aerial parts and root bark extracts of E. amoena showed that the extracts were active against Staphylococcus aureus (Chhabra, Shao, Mshiu, & Uiso, 1981; Khan, Ndaalio, Nkunya, Wevers, & Sawhney, 1980). These findings could be used to corroborate traditional uses of E. amoena extracts as traditional medicines for gastrointestinal problems such as blood diarrhoea, diarrhoea, dysentery, stomach ache and stomach problems and sexually transmitted infections such as genital ulcers, gonorrhoea and venereal diseases (Bruschi et al., 2011; Hedberg et al., 1982).

Antitrypanosomal activity

(Freiburghaus et al., 1996) evaluated the antitrypanosomal activities of dichloromethane, methanol and water extracts of E. amoena leaves, root and stem bark against Trypanosoma hrucei rhodesiense using in vitro assays with commercial drugs, pentamidine isethionate and suramin as positive controls. The extracts exhibited activities against the tested pathogen with minimum inhibitory concentration (MIC) values ranging from ≤19.0 μg/ml to ≥167.0 μg/ml (Freiburghaus et al., 1996).

Similarly, (Räz et al., 1996) evaluated the antitrypanosomal activities of dichloromethane extracts of E. amoena leave and the compound chrysosplenetin isolated from the species against the bloodstream forms of Trypanosoma brucei rhodesiense using in vitro assays. Both the extract and the compound exhibited activities with half-maximal inhibitory concentration (IC₅₀) values of 7.0 μg/ml and 1.1 μg/ml, respectively. This pharmacological evaluation is of importance in the traditional uses of E. amoena against sleeping sickness in Uganda and future research focusing on control and management of sleeping sickness and related vector-borne parasitic diseases in the tropics (Freiburghaus et al., 1996; Räz et al., 1996).

Cytotoxicity activities

(Freiburghaus et al., 1996) evaluated the cytotoxicity activities of dichloromethane and methanol extracts of E. amoena leaves, root and stem bark on a human fibroblast cell line (W1-38) with pentamidine isethionate and suramin as positive controls. The extracts exhibited activities with IC₅₀ and maximum tolerated concentration (MTC) values ranging from ≤0.9 μg/ml to 9.6 μg/ml and 19.0 μg/ml to 112.0 μg/ml, respectively (Freiburghaus et al., 1996).

(Cosam et al., 2004) assessed the cytotoxicity activities of 20% aqueous ethanol extract of E. amoena stem bark using the brine shrimp lethality test. The concentrations killing 50% of the brine shrimps (LC₅₀) was 65.0 µg/ml (Cosam et al., 2004).

(Sempombe et al., 2014) evaluated the cytotoxicity activities of ethanol and petroleum ether extracts of E. amoena leaves and root bark against a 3-cell line panel consisting of TK10 (renal), UACC62 (melanoma) and MCF7 (breast) cancer cells using the sulforhodamine B assay with etoposide as a reference standard.

The extracts exhibited activities with half-maximal growth inhibition concentration (GI₅₀), total growth inhibition (TGI) and LC₅₀ values ranging from 9.3 μg/ml to 13.0 μg/ml, 22.3 μg/ml to 26.5 μg/ml and 40.3 μg/ml to 86.1 μg/ml, respectively (Sempombe et al., 2014).

These findings imply that E. amoena extracts may have deleterious health implications and detailed toxicological evaluations are required to determine toxicity and/or any side effects associated with consumption of the species as herbal medicine.

Conclusion

This review showed that E. amoena is characterized by several phytochemicals and the species exhibited antibacterial, antitrypanosomal and cytotoxicity activities. However, the majority of these biological activities lack of bio guided isolation strategies and mechanisms of action. Therefore, future research should focus on pharmacokinetics, mechanisms of action and structural activity relationships of phytochemical compounds of the species. Future research should also focus on animal experiments aimed at assessing the toxicity and clinical efficacy of species extracts.