The Ethnobotany and Chemistry of South African Meliaceae: A Review

Meliaceae are widely distributed across the world in tropical or subtropical climates and are of considerable ethnobotanical importance as sources of traditional medicine and cosmetics. This comprehensive review summarizes the ethnobotanical uses and chemistry of 12 South African species, belonging to six genera: Ekebergia, Nymania, Entandrophragma, Pseudobersama, Trichilia, and Turraea. Eight of the species have ethnomedicinal records, classified into 17 major disease categories. The ethnomedicinal uses comprise 85 ailments dominated by gastrointestinal complaints, followed by gynaecological and obstetrics related problems. Chemical records were found for 10 species, which describe nine classes of compounds. In nearly all South African Meliaceae, limonoids are the predominant constituents while triterpenes, sterols, and coumarins are also common. The widest range of use-records and medicinal applications are found with the two most chemically diverse species, Ekebergia capensis and Trichilia emetica. Of the chemical compounds identified in the various plant organs of the 10 species of South African Meliaceae for which data are available, 42% was found in bark and 17% in seeds. Roots represent 35% and bark 33% of the organs that are used medicinally, and they are typically prepared as decoctions or infusions. Root and bark harvesting are destructive so that it may be important to examine the chemistry of plant parts such as wild-crafted leaves and fruits.


Introduction
Ethnobotany is the cultural study of the practical uses of a region's plants by the local people. It is interdisciplinary and can often progress into a lab-based collaborative project with the vision of benefiting modern society in the form of wild food crops, pharmaceuticals, nutraceuticals, or cosmetics [1]. Furthermore, by recording traditional plant use, indigenous knowledge and belief systems are conserved [2] and incentives for biodiversity conservation are realized. Unfortunately, the floras that are used traditionally are the most likely to be destroyed or threatened by over-exploitation. The management of plants that are utilised by local people or small grass-roots level industries may be facilitated by a more complete understanding of the dynamics of people-plant interactions [2][3][4].
The culture of plant-based subsistence is rapidly becoming a rarity in the modern world. Hence, the cultures of the African people represent a minority that have continued practicing holistic environmentalism that utilises raw plant-based materials for food, medicines, as pesticides or tools and in spiritual pursuits including rituals [5]. In the modern day, most South Africans rely on traditional medicine as a first line of treatment. This is chiefly due to its affordability, accessibility, and the high level of knowledge by local traditional healers [6,7]. In this regard, about 3000 out of over 20,000 species of higher plants in South Africa are used in traditional medicine [8]. The botanical prescriptions made by the archetypical traditional healers in South Africa are collectively called 'muthi' and are generally distributed out of informal markets.
Ethnobotanical uses and prescriptions of South African Meliaceae are reported in Table 1. Although six genera and twelve species are recognised in South Africa, only eight species from five genera have recorded ethnomedicinal uses, giving a total of 85 different ethnomedicinal uses summarised from published records. Out of the functional uses, Trichilia emetica Vahl demonstrated the highest utility, followed by Ekebergia capensis Sparrm ( Figure 1). Both were frequently cited as being used as shade trees and for ornamental purposes, as well as for furniture, timber, and cosmetics (Section 2.1.5).
Plants 2021, 10, x FOR PEER REVIEW 3 of 46 in cardiovascular function, and respiratory, urinary, gastrointestinal, dermatological, and oral infections [12,30]. Ethnobotanical uses and prescriptions of South African Meliaceae are reported in Table 1. Although six genera and twelve species are recognised in South Africa, only eight species from five genera have recorded ethnomedicinal uses, giving a total of 85 different ethnomedicinal uses summarised from published records. Out of the functional uses, Trichilia emetica Vahl demonstrated the highest utility, followed by Ekebergia capensis Sparrm (Figure 1). Both were frequently cited as being used as shade trees and for ornamental purposes, as well as for furniture, timber, and cosmetics (Section 2.1.5). In the context of strictly therapeutic applications, E. capensis represents an important complement to South African materia medica [6]. The parts of E. capensis used traditionally vary according to end-use, but range from bark, leaf, fruit, root, wood to twig. Such applications include the treatment of epilepsy, malaria, pain, skin ailments, and gastrointestinal, respiratory, cardiovascular, and reproductive problems ( Table 1).
The most commonly used organs are the bark or root bark, administered as a decoction that is boiled in about 2 L of water and taken as an emetic for coughs, heartburn, and respiratory chest complaints [6]. When a poultice is made from the crushed bark, it is combined with flour and water as a caking agent and applied as a skin scrub for use as a In the context of strictly therapeutic applications, E. capensis represents an important complement to South African materia medica [6]. The parts of E. capensis used traditionally vary according to end-use, but range from bark, leaf, fruit, root, wood to twig. Such applications include the treatment of epilepsy, malaria, pain, skin ailments, and gastrointestinal, respiratory, cardiovascular, and reproductive problems ( Table 1).
The most commonly used organs are the bark or root bark, administered as a decoction that is boiled in about 2 L of water and taken as an emetic for coughs, heartburn, and respiratory chest complaints [6]. When a poultice is made from the crushed bark, it is combined with flour and water as a caking agent and applied as a skin scrub for use as a topical blood purifying agent for abscesses, boils, and in hot water infusions for pimples [13]. Different parts of the plant could either be used alone or in combination with other species. The bark powder and leaf decoctions are used in the treatment of intestinal worms and epilepsy [13,30,40]. In this regard, approximately 200 mL of the aqueous leaf infusion is drunk as a purgative parasiticide. Furthermore, the bark and root are combined to treat gastritis, dysentery, heartburn, and as an expectorant [6,8,12]. The bark is also used in rituals to guard tribal chiefs against witchcraft and taken orally as a love charm emetic [13].

Scabies
Root and leaf NR [12,41] Abscess and boil Bark Crushed bark added to flour and water poultices is applied [13,51] Pimples Bark Crushed bark in hot water infusion is drunk and used as a wash [13,51] Skin ailments Leaf NR [37]

Bloody stool Bark
Bark is macerated with bark of Diospyros lycioides Desf. and extract is drunk [53] Emetic and heartburn Bark and root Bark or root decoctions are taken as emetics [6,43,54]

Back pain Bark
A teaspoon of pulverised bark boiled in a cup of milk is allowed to cool and strained, then half a cup of the extract is taken as an enema in the early morning [12,13] Fever Root Root decoction is taken orally [12,65] Toothache NR NR [14] Antimicrobial

Gonorrhoea and Syphilis Leaf
Handful of leaves is boiled with a handful of Albizia adianthifolia leaves in 2 L water and half a cup of the decoction is taken daily [27,43,53,66] Leprosy NR NR [65]

Cardio-Vascular
Blood purifier Bark Bark is taken as an enema for men [43] Dermatological Bruises and eczema Leaf or fruit Leaf or fruit poultice is applied topically [65] Gastro-Intestinal Bloody diarrhoea Bark Bark decoction is taken daily [53,65] Purgative and stomach complaints Bark or root Bark infusion is taken as an enema or root decoction is taken orally [13,65,67] Gynaecological and Obstetrics; Genital system

Abortifacient Bark
Bark infusion or decoction is taken orally or used as an enema [65,67]

Gastric ulcer Bark
Crushed bark mixed with salt and ginger is added to porridge and taken twice daily [38] Hernia Root Crushed root is added to porridge and taken orally [38] Inflamed anus Bark Pulverized bark puffed into the anus [30] Jaundice Root Root decoction is taken daily for 3 days, chopped roots are also mixed with honey and used as a bath [38,70] Laxative Bark Bark is mixed with eggs and taken orally to clean the stomach [78] Purgative Bark Bark infusion or decoction is used as an enema or taken orally [53,67,76] Stomach complaints Bark Bark infusion or decoction is taken orally or administered as an enema [43,53,54,67] Gynaecological and Obstetrics; Genital system Abortifacient Bark Bark infusion is taken [67,71] Bark and root One handful of crushed bark and root in a litre of milk and Coca Cola mixture is boiled for 15 min and taken orally [27] Breast pain Leaf Leaf decoction is used to bath [38] Dysmenorrhoea Leaf Leaf decoction added to Tamarindus indica L. or lemon is taken orally for 7 days [38,79] Fertility Leaf Leaf decoction with Combretum molle R. Br. ex G.
Don is taken orally [38] Bark Crushed bark mixed with the same amount of Gymnosporia senegalensisa root is boiled and decoction is used as an enema [27] Labour pain Leaf Hot leaf decoction is used to massage the belly of a woman during labour to ease pain until she delivers [27] Sterility Root Powdered root with ginger and salt is taken as a porridge [38]

Musculo-Skeletal
Lumbago Bark or leaf Bark or leaf maceration is taken as an enema [12,30] Paralyses Root Crushed root is mixed with porridge and taken orally [38]

Eye infection Leaf and bark
Leaf and bark decoction is used for eye cleansing for 2 days [38] Respiratory system Cardiac problems Leaf Leaf decoction is taken orally [80] Chest pain Leaf Leaf decoction is used in a steam bath or rubbed on the chest [38] Cough Bark and root Bark and root decoction is drunk [81] Pneumonia Root or leaf Root or leaf decoction is taken orally or used as a bath for 12 days [37,38] Trauma

Fracture Seed
Oil from the seed is rubbed into incisions on broken limbs and baked pulverized root of Sideroxylon inerme L.
is applied [8,12,13,82] Stiffness or sprains Bark Bark extract is applied topically [69] Wound Seed Oil from the seed is applied to prevent infection from maggots [37] Urinary system Kidney problem Bark Bark decoction is administered as an enema [43] Renal

Rheumatism Root
Root maceration is taken orally [8,12,13,75,76] Respiratory system Cardiac problems Root Root maceration is taken orally [12,13,47,75,76]  Remedies made from the South African Meliaceae are used to treat a wide variety of medical conditions in humans, as well as for ritual purposes. They are also used in ethnoveterinary treatments. Most of the species had more than one therapeutic use, with T. emetica having the highest number of uses and categories (50 and 15, respectively), followed by E. capensis (29 and 13, respectively). The lowest number of uses and categories was recorded against T. obtusifolia (Figure 1). The highest number of citations for ethnomedicinal uses was recorded against T. emetica (31) followed by E. capensis (30), T. dregeana (12), T. nilotica (9), T. obtusifolia (6), N. capensis (5), and E. caudatum (2) (Figure 1). Eighty-seven different ailments grouped into 17 major categories which are gastro-intestinal; gynaecological and obstetrics; dermatological; analgesic; antimicrobial; respiratory system; magic; trauma; urinary system; nervous system; anthelmintic; ethnoveterinary; cardio-vascular; ear, nose and throat; ophthalmic; and cytological were recorded in this study ( Figure 2). Most of the species of South African Meliaceae are mostly used in the treatment of gastrointestinal ailments followed by gynaecological and obstetrics related ailments ( Figure 2). However, there was no ethnomedicinal record found for four of the species (E. pterophylla, P. mossambicensis, T. pulchella, and T. streyi).
Remedies made from the South African Meliaceae are used to treat a wide variety of medical conditions in humans, as well as for ritual purposes. They are also used in ethnoveterinary treatments. Most of the species had more than one therapeutic use, with T. emetica having the highest number of uses and categories (50 and 15, respectively), followed by E. capensis (29 and 13, respectively). The lowest number of uses and categories was recorded against T. obtusifolia (Figure 1). The highest number of citations for ethnomedicinal uses was recorded against T. emetica (31) followed by E. capensis (30), T. dregeana (12), T. nilotica (9), T. obtusifolia (6), N. capensis (5), and E. caudatum (2) (Figure 1). Eighty-seven different ailments grouped into 17 major categories which are gastrointestinal; gynaecological and obstetrics; dermatological; analgesic; antimicrobial; respiratory system; magic; trauma; urinary system; nervous system; anthelmintic; ethnoveterinary; cardio-vascular; ear, nose and throat; ophthalmic; and cytological were recorded in this study ( Figure 2). Most of the species of South African Meliaceae are mostly used in the treatment of gastro-intestinal ailments followed by gynaecological and obstetrics related ailments ( Figure 2). However, there was no ethnomedicinal record found for four of the species (E. pterophylla, P. mossambicensis, T. pulchella, and T. streyi). An example of the use of E. capensis in multi-therapeutic combinations with other species is the decoction that is made from a combination of E. capensis leafy twigs and I. oubanguiensis, which is taken orally and used as a wash to treat dystocia [30]. Bryant [54], also described how the bark decoction of E. capensis is mixed with roots of E. natalensis, to be taken orally to treat respiratory problems. More examples of species combinations in multi-therapeutics with E. capensis are provided in Table 1. Preparation of herbal remedies using more than one plant species can be attributed to the synergistic or additive effects that could occur during the treatment [88].
In contrast to E. capensis, E. caudatum has minimal presence in South African materia medica. The root decoction is being used as a remedy for gonorrhoea, while the burnt fruit is mixed with Vaseline and applied topically to treat genital warts [62]. This is not the only record of dry heating/burning as a materia medica modality.
In some applications, N. capensis processing involves a roasting step, i.e., according to Von Koenen [64] the root is roasted, pulverized, and applied topically to treat wounds and relieve knee pain. However, medical uses of N. capensis broaden to include a root decoction taken orally to treat kidney and stomach complaints, as well as nausea. The leaf decoction is also taken orally as a herbal remedy for convulsion [63,89].
Trichilia dregeana is an important medicinal plant with all of the parts used traditionally [55]. It is used as a herbal remedy for the treatment of syphilis, bloody diarrhoea, skin diseases, rheumatism, as an abortifacient, blood cleanser, and as fish poison ( Table 1). The bark infusion or maceration is used as an enema for the treatment of kidney problems, bronchial inflammation, skin diseases, as well as general cleaning [13,43,52]. The bark is eaten as a purgative or for procuring abortion and also as a fish poison [67]. The leaf decoction is taken orally as a herbal remedy for syphilis [13,66].
Similar to E. capensis, species in Trichilia are also strongly represented in the ethnobotanical tradition of South African people. Trichilia emetica is a multipurpose tree that is widely distributed throughout Africa, meaning it is not exclusively a South African medicine [38]. All plant parts, the leaf, twig, bark, flower, wood, root, and fruit of T. emetica are used (Table 1). It is used as a purgative, an antipyretic, antiepileptic, and antimalarial agent [72]. The twig, trunk, wood, and root are chewed as herbal remedy for dental care [30]. The powdered bark is taken orally as a remedy for infertility and also to ease labour pain [27,38]. The bark decoction or infusion is also used to treat various ailments including dysentery, gastrointestinal problems, breast pains, back pains fever, malaria, and as a purgative ( Table 1). The bark decoction is used by the Xhosa tribe as an enema to treat kidney problems [12].
In other applications, a hot leaf infusion of T. emetica is rubbed on the affected part to treat burns while the leaf decoction is taken orally as a remedy for dysmenorrhoea and syphilis [13,38]. The leaves are also used as a poultice for wound healing, skin problems, and contusions [29,52]. The leaves can also induce drowsiness or sleep at night when placed in the bed [38]. The root decoction is used as a herbal remedy for colds and bronchial inflammation, chest pain, fever, pneumonia, jaundice, gastrointestinal infections, and sexually transmitted diseases ( Table 1). The fruit is used as a herbal remedy for eczema [13,82]. Pulverized seeds of T. emetica are boiled and the oil is rubbed on the affected part to treat rheumatism and leprosy [46]. However, the combination of two or more organs of T. emetica can also be used as a herbal remedy ( Table 1) that is allegedly more potent than the individual parts. The decoction of stem, root, and bark is taken orally as a herbal remedy for whooping cough and ulcers [38,81]. The leaf and bark decoction of T. emetica is rubbed on the eye to treat an eye infection [38].
Similar to other taxa in Meliaceae, the bark and root of T. floribunda is used as a remedy for a broad range of ailments (Table 1). It is boiled in water and taken orally as an emetic and herbal remedy for urethral infection [37,54,83]. A bark infusion of T. floribunda is also taken orally to induce a state of trance prior to rituals [75]. The root decoction is taken orally as a remedy for cough and hardened abscess [37], while the root maceration is taken orally to treat rheumatism, cardiac problems, ascites, and dropsy [8,13]. The root and bark decoction are taken orally as a purgative [12,37].
The root decoction of T. nilotica is taken orally as a remedy for headaches, hardened abscess, indigestion, gonorrhoea, sterility, dysuria, jaundice, as a poison antidote, and against intestinal worms [30,67,70,81]. The root decoction is used as a mouth wash for toothache and the ash of the burnt root is applied topically as a snakebite antidote [30,84]. The root infusion is taken orally to treat venereal diseases, abdominal pain, constipation, inflammation of navel cord, and to prevent abortion [8,30,67]. The root infusion is taken orally with honey to treat schistosomiasis, hernia, and bilharziasis, while in ethnoveterinary medicine, the root infusion is used as an anthelmintic for dogs [8,81]. The root powder is taken orally in beer or porridge as an aphrodisiac, it could also be used as a remedy for dysmenorrhea, epilepsy, and dyspnoea [67]. The leaf decoction is taken orally as a remedy for abdominal pain and diarrhoea, while the leaf infusion is taken orally as a remedy for dizziness [30,37,85]. The leaf infusion of T. nilotica is taken orally and the smoke from burnt leaves is inhaled to calm an 'insane person', while the leaf paste is applied to the eyelid to treat eye problems [67].
The leaves, bark, and root bark of T. obtusifolia are macerated together in hot water and taken with porridge as a remedy for stomach and intestinal complaints [86]. Due to the diverse use of E. capensis, T. dregeana, T. emetica, T. floribunda, and T. obtusifolia as herbal remedies, the bark is sold in informal herbal medicine markets as traditional medicines in Gauteng and KwaZulu-Natal provinces in South Africa [90].

Categories of Uses
Remedies made from South African Meliaceae are used to treat a wide variety of medical conditions in humans as well as for ritual purposes. They are also used in ethnoveterinary treatments. All of the species had more than one therapeutic use, with T. emetica having the highest number of uses and categories (50 and 15, respectively), followed by E. capensis (29 and 13, respectively) and the lowest number of uses and categories was recorded against T. obtusifolia (Figure 1). The highest number of citations for ethnomedicinal uses was recorded against T. emetica (31) followed by E. capensis (30), T. dregeana (12), T. nilotica (9), T. obtusifolia (6), N. capensis (5), and E. caudatum (2) (Figure 1). Eighty-seven different ailments were grouped into 17 major categories including gastrointestinal; gynaecological and obstetrics; dermatological; analgesic; antimicrobial; respiratory system; magic; trauma; urinary system; nervous system; anthelmintic; ethnoveterinary; cardio-vascular; ear, nose, and throat; opthalmic; and cytological were recorded in this study ( Figure 2). South African Meliaceae are mostly used in the treatment of gastrointestinal ailments followed by gynaecological and obstetrics related ailments ( Figure 2). However, there was no ethnomedicinal record found for four of the species (E. pterophylla, P. mossambicensis, T. pulchella, and T. streyi).

Plant Parts Used
The plant parts of South African Meliaceae used in making herbal remedies were the root, bark, leaf, fruit, seed, twig, and trunk. Roots (35%), followed by barks (33%) and leaves (25%), were the most frequently used plant parts in preparation of the recorded herbal remedies (Figure 3a). Several studies reported roots to be more effective than other herbal plant parts. Hence, these were most frequently sourced [5,[91][92][93]. This practice can also be linked to the scientific reasoning that roots and other underground parts contain high concentrations of bioactive compounds [94]. However, harvesting of roots for medicinal purposes is not sustainable as it threatens the existence of many medicinal plants which could lead to depletion of the plants. It is well documented by conservationists that medicinal plants mostly sourced for their root parts and bark are likely to be the most threatened by over-exploitation [95].

Mode of Herbal Preparation
Decoction (47%) was the most common mode of preparation recorded followed by infusion (16%), direct use as herbal powder (14%), poultice (12%), and maceration (11%) (Figure 3b). Decoction (boiling of the plant material) has been reported to be the most commonly used method of preparation in herbal medicine as it is believed that boiling extracts all of the potential bioactive compounds from the plant [96][97][98][99][100]. Moreover, decoction was reported to be the most common method of herbal preparations in South Africa [6]. Most of the remedies were administered orally followed by topically in the case of wound and skin infections, while some are sniffed into the nose (Table 1). conservationists that medicinal plants mostly sourced for their root parts and bark are likely to be the most threatened by over-exploitation [95].

Mode of Herbal Preparation
Decoction (47%) was the most common mode of preparation recorded followed by infusion (16%), direct use as herbal powder (14%), poultice (12%), and maceration (11%) (Figure 3b). Decoction (boiling of the plant material) has been reported to be the most commonly used method of preparation in herbal medicine as it is believed that boiling extracts all of the potential bioactive compounds from the plant [96][97][98][99][100]. Moreover, decoction was reported to be the most common method of herbal preparations in South Africa [6]. Most of the remedies were administered orally followed by topically in the case of wound and skin infections, while some are sniffed into the nose (Table 1).

Other Uses
South African Meliaceae have also been reported to be useful for other purposes apart from medicinal uses. Ekebergia capensis, E. pterophylla, Entandrophragma caudatum, T. dregeana, T. emetica, T. floribunda, and T. obtusifolia are used as ornamental plants in gardens and on roadsides to create shade, wind breaks, and soil conservation ( Table 2). The timber of E. capensis, E. caudatum, P. mossambicensis, and T. dregeana are mostly sought after by the furniture industry since they are soft, easy to work with, and durable ( Table  2).

Other Uses
South African Meliaceae have also been reported to be useful for other purposes apart from medicinal uses. Ekebergia capensis, E. pterophylla, Entandrophragma caudatum, T. dregeana, T. emetica, T. floribunda, and T. obtusifolia are used as ornamental plants in gardens and on roadsides to create shade, wind breaks, and soil conservation ( Table 2). The timber of E. capensis, E. caudatum, P. mossambicensis, and T. dregeana are mostly sought after by the furniture industry since they are soft, easy to work with, and durable ( Table 2). Wood is used in furniture industry [12,40] Firewood and charcoal production Wood Wood is used in cooking [12,40] Animal feed Fruit and leaf Birds feed on fleshy parts of the fruit, while the leaf is used as a fodder [12,40] Shades and wind break Whole plant It serves as an ornamental tree planted in gardens and roadsides for shades, as well as for wind break and soil conservation [40,43] Edible caterpillar Whole plant Caterpillars are gathered from the plant and prepared as food [43,101]

Food condiments Fruit
Fruit content is cooked with vegetables, fruit pulp is eaten as sour milk, while the oil made from the fruit pulp is used in cooking vegetables and other relishes [43,65] Polish Fruit and seed Oil made from seed and fruit pulp is used to polish women's clothes made from leather, furniture, and other household implements made from wood [43] Soap and cosmetics Seed Oil from seeds is used to make soap, cosmetics, and candles [43,75,103] Forage or fertilizer Seed Residue from seeds after oil extraction is used as a fertilizer or animal feed [65] Fruit Fruits are eaten by birds and bats [75] Drink Seed aril Seed aril is pounded and made into a sauce or sweet drink [65] Shade Whole plant Whole plant is used to create shady avenue and as an ornamental tree [65,75] Fishing Seed Bright-coloured seed is used as bait for fishing [65] [87,101] The wood of E. capensis, P. mossambicensis, and T. nilotica are used for charcoal and firewood for cooking (Table 2). Birds feed on the fleshy part of the fruit of E. capensis and the leaves are used as a fodder for domestic stock and game [12,40]. Edible caterpillars gathered from E. capensis are eaten as food by the Vhavenda [43,101]. Nymania capensis is used as a garden plant and also as a source of forage for goats [89]. The seeds of T. dregeana and T. emetica are known for their high fat content, hence the fat is used in soap making, as a body ointment, as polish, hair oil, and in cooking [43,75,103]. The seed arils of T. dregeana and T. emetica are cooked as vegetables or crushed for the milky juice which is taken with side dishes or as a drink [8,101]. In northern KwaZulu-Natal, the wood of T. dregeana is used to carve birds and animals which are sold along roadsides [8].
The wood of T. emetica is used to carve meat dishes, bowls, spoons, head rests, and animal carvings in Maputaland [4]. The leaves of T. emetica are eaten by wild animals and also worn in burial rituals by the Zulu [13,82]. The VaVhenda people in South Africa use the wood to construct the frame of an African traditional musical instrument ('mbila'), while oil from T. emetica is applied on the instrument to soften the animal skin used for the instrument [82]. Saka and Msonthi [106] reported the juice from T. emetica seeds mixed with other edible plants to be used as multivitamins in cases of malnutrition.
The wood of T. floribunda is used for making traps, while stems of T. nilotica are used for handcrafts [107]. Turraea obtusifolia can also be used as a container plant in landscape design [76].

Reported Active Compounds
Several limonoids and other secondary metabolites of appreciable biological activities have been reported in South African species of the Meliaceae. The extracted compounds and parts extracted are represented in Table 3. Chemical studies for 10 out of the 12 South African Meliaceae were found. The two species that had no records are T. streyi and T. pulchella.
The compounds are classified according to nine categories of chemical class which are: (1) Limonoids, (2) triterpene, (3) coumarin, (4) glycoflavonoid (glycoside), (5) phenolic aglycone, (6) sterol (phytosterol), (7) pregnane, (8) protolimonoid, and (9) sesquiterpene. The highest reported chemical classes were limonoids followed by triterpenes and sterols. However, sterols are common in higher plants. On the other hand, a significant number of triterpenes, coumarins, and limonoids are described in South African species for the first time and their naming is etymologically related to the genus or species. Unsurprisingly, the richest diversity of new metabolites include a heterocyclic moiety in the form of a lactone, coumarin or furan.
Novel types of limonoid of the ekebergolactone class were first described from a species of Ekebergia and received the name capensolactones, which were isolated among others (Table 3) from the leaves, seeds, and stem bark of E. capensis [31,33,108,109]. From E. pterophylla, more new limonoids were described and given initials taken from the genus and species name (EP1-EP6), which are closely related to methyl angolensate and similar to those of other Ekebergia species [110,111]. Furthermore, complex limonoids referred to as Nymania 1-4 were isolated from the bark of N. capensis [112], reiterating the etymological genesis.
All of the species in the current study, except one, were rich sources of new limonoids, often described nowhere else in the world. While no limonoids were reported from P. mossambicensis, the nine other species investigated so far constitute valuable sources of these compounds [113][114][115]. The limonoids of E. caudatum were named phragmalins after the genus [116]. From seeds of T. dregeana, the limonoids include dregeana 1-4 [117]. Several limonoids from other South African Meliaceae were assigned in the stem bark of T. emetica, and previously undescribed compounds including trichirokin and trichilins A-G [24,118]. Then, in the genus Turraea several limonoids were also reported, such as turraflorins A-I and the floribundins A-F (names assigned in the current review, Table 3) from the root of T. floribunda, nilotin from the root and stem bark of T. nilotica [119,120] or prieurianins from seeds of T. obtusifolia [121][122][123].
The limonoid class, per se, was first isolated from citrus, typically from leaves, fruit, and peel of lemons, limes, oranges, pomelos, grapefruits, bergamots, and mandarins (Manners 2007; Hamdan 2011; Wang 2016). Citrus limonoids represent the traditional limonoid that is known as limonin or its derivatives, which occur in aglycone and glycoside forms [124]. They are distinctly different from the ekebergolactone class of limonoid (that is a pentaneotriterpenoid) represented strongly in South African Meliaceae. These include Nymania limonoids and capensolactones. Therefore, it is expected that a functional overlap is minimal in the context of biology.
A third category of limonoids, ekebergins 1-10 from E. capensis are triterpenes and have demonstrated anti-plasmodial activity in an in vivo mouse model, giving moderate parasitemia suppression [33]. However, the ekebergins have a structural feature that classifies them as nortriterpenes, but conveys a structure that is between the traditional limonoid and a triterpene. In this regard, some researchers classify them as limonoids, whilst others call them nortriterpenes [125].
The protolimonoids are also of triterpenoid origin but are classed as steroids. Protolimonoids were isolated and assigned as new compounds from the root and stem bark of T. nilotica and named according to the species as niloticin and dihydroniloticin [119,120]. Melianone type protolimonoids were isolated and identified from E. caudatum [113][114][115] and T. obtusifolia, which also had turraeanthin [121][122][123].
The species that expressed the highest steroid composition was T. emetica, which produced an extract comprising C21 steroids known as 17β-ethylandrostane derivatives or simply pregnanes. Nine pregnanes are known thus far from T. emetica [126] and one from E. capensis [33]. The pregnanes are agonists of the nuclear pregnane x receptor, which controls the elimination of toxins from the body by xenobiotic monooxygenase metabolism (cytochrome P450 3A) [127]. Activation can cause a variety of effects that include promotion of elimination of toxins that have similar structures. However, drug-drug interactions can also result, preventing co-administered therapies from being metabolised. The net outcome is an increase in drug half-life for some types of xenobiotics, which can be positive in terms of prolonging efficacy effects, but negative by augmenting the risk of toxicity [128].
South African Meliaceae also express several common triterpenes of the oleanane type and common sterols such as β-sitosterol. For example, the type, as well as common triterpenes β-amyrin, β-amyrone, oleanonic acid, lupeol, and other common sterols were reported from the wood and bark of E. pterophylla [108]. Ergosterols were isolated from twigs and leaves of P. mossambicensis [129], cycloarten-diol triterpenes from the leaves of T. dregeana [130], and sterols from the stem bark of T. emetica [24]. The common triterpene oleanolic acid and its derivatives from E. capensis demonstrated cytotoxicity against cancer cell lines and moderate antiplasmodial activity that may be related to the cytotoxic activity [31]. However, novel acyclic triterpene derivatives of cosatetraene or squalene are also reported in E. capensis. These hydroxylated structures are atypical in that they are tail-to-tail sesquiterpenes that demonstrate noteworthy antiplasmodial activity comparable to the ekebergin limonoid mentioned previously [33]. Some sesquiterpenes have also demonstrated these biological effects. Kurubasch aldehyde is another antiplasmodial terpene isolated from T. emetica, which is a hydroxylated humulene that is a potent inhibitor (IC 50 7.4 µM) of the S180 cancer cell line and demonstrates a modest anti-protozoal effect [131].
South African Meliaceae are also a reservoir of rare coumarins. The pterophyllin 1-5 series was isolated from the wood and bark of E. pterophylla [132]. These chemical species belong to the group of furocoumarins. The pterophyllins are moderate antifungal compounds which are active against fruit pathogens [133]. Coumarins were also reported in E. capensis, one of which is ekersenin. This compound was first described in E. senegalensis but is now known to be widespread in African Meliaceae. Several derivatives of ekersenin were isolated from the stem bark, wood, and root of E. capensis [31][32][33][34][35]. While the cytotoxic effects against cancer cell lines have not yet been tested, it will be a worthy undertaking since a related limonoid demonstrated potent inhibition (IC 50 6.8 µM) against the A2780 cell line [134], although the authors did not specify the mechanism nor did they screen against healthy cells, hence toxicity was not determined.

Structures of Some of the Isolated Compounds
Most of the reported limonoids are summarised into series according to their structure (Table 4 and Figures 6-16) or with common structural themes. Floribundin naming is used here for the first time.       [117,136]. Figure 8. Dregeanin series of limonoids reported from South African Meliaceae [117,136].     [113,116]. Figure 12. Phragmalin, phragmin, and bussein series of limonoids reported from South African Meliaceae [113,116]. Plants 2021, 10, x FOR PEER REVIEW 37 of 46 Figure 13. Rohituka series of limonoids reported from South African Meliaceae [24,117,118]. Figure 13. Rohituka series of limonoids reported from South African Meliaceae [24,117,118].

Materials and Methods
The recorded ethnobotanical uses and isolated compounds were based on a search of scopus and science-direct electronic databases, pubMed, reference libraries, conference papers, ethnobotanical books, dissertations, theses, and scientific articles. All of the

Materials and Methods
The recorded ethnobotanical uses and isolated compounds were based on a search of scopus and science-direct electronic databases, pubMed, reference libraries, conference papers, ethnobotanical books, dissertations, theses, and scientific articles. All of the relevant papers were included in this study except those that were not peer reviewed and those containing species that are not indigenous to South Africa. The ethnomedicinal uses are classified into 17 major categories, based on Moffett's [150] classification, while the compounds were categorised into nine main chemical classes and the structures drawn using ACD/ChemSketch Freeware (Windows platform).

Conclusions
The species of South African Meliaceae have been reportedly used for a diversity of purposes from medicinal (including human and animal), to rituals, to functional uses (making of implements, furniture, oils, and dyes). A total of 85 different medicinal uses were recorded, and T. emetica is the most frequently used, followed by E. capensis. Several compounds have been isolated from South African Meliaceae. A total of 188 compounds belonging to nine classes were recorded from various plant parts. The highest number of compounds belonged to the limonoids class, followed by sterols. There was no record found for the chemistry of T. streyi and T. pulchella.
The high chemical diversity of these species may be related to the high diversity of therapeutic uses recorded. South African Meliaceae are mostly used in the treatment of gastro-intestinal ailments followed by gynaecological and obstetrics related ailments. The most common mode of herbal preparation was decoction followed by infusion. The roots followed by bark are mostly commonly used in the preparation of the remedies, whereas most of the compound isolation work focused on the bark followed by seeds -this may be a consequence of logistical difficulty in obtaining roots for chemical study.
The ethnomedicinal uses recorded in this study are of value for bioprospectors or synthetic chemists looking for chemical scaffolds as precursors to biologically enhanced derivatives. However, the current review also strengthens the call for increased conservation practice, which is due to the fact that root and bark harvesting are destructive. Hence, it may be important to examine the chemistry of plant parts such as leaves and fruits.

Conflicts of Interest:
The authors declare no conflict of interest.