Ethnomedicinal Uses, Phytochemistry and Pharmacological Properties of Suregada Genus: A Review

Plants of the Suregada Roxb. ex Rottler (formerly Gelonium Roxb. ex Willd) are utilized to treat various ailments, namely, hepatic, gum diseases, pyrexia, eczema, and venereal diseases. This review links the reported compounds to ethnomedicinal uses through pharmacological activities. The compounds possess anticancer, anti-allergic, antibacterial, anti-inflammatory, antioxidant, and anti-HIV properties. From the previous reports, 32 known species of the Suregada genus have been investigated morphologically, and nine were investigated for their phytochemistry and pharmacology. Phytochemistry, ethnomedicinal, and pharmacological uses of the other 23 Suregada species are not known and/or not reported. In this review, abietane diterpenoids are the main compounds expressed by the Suregada, accounting for 71 of the 114 reported compounds. Ten triterpenoids and sterols, one aliphatic, two lignans, five flavonoids, and twenty-one nitrogen-containing compounds have been reported from the genus.


Introduction
Suregada Roxb.ex Rottler (formerly Gelonium Roxb.ex Willd.)species are shrubs or small trees occurring in the forest, deciduous forest, or thicket with 32 accepted species, extending from Africa and Madagascar through India to southern New Guinea, China, Philippines, and northern Australia [1].
Based on morphology, Suregada was placed in Euphorbiaceae-Crotonoideae in the tribe Gelonieae with the monotypic Cladogelonium Leandri of Madagascar by Radcliffe-Smith in genera Euphorbiacearum [2,3].Wurdack et al. stated that the relationship between these two genera was endorsed in a molecular phylogenetic study and was sister to the main clade of Crotonoid genera [4].
The genus Suregada is highly distinctive and cannot be confused with any other genus of tree or shrub in Sub-Saharan Africa.The combination of translucent gland dots in the leaves, leaf-opposed fasciculate or glomerulate inflorescences, and the node encircled by stipules (or stipular scars) separates it not only from all other genera in Euphorbiaceae but from all other genera with alternate simple leaves [2,3].Suregada is best recognized by its 'cytotoxic activity' OR 'antiviral', OR 'anti-inflammatory'.The search terms were run separately or as a combination of terms depending on the database used for the period between 2000 and 2022.The search resulted in over 100 reports mostly in the English language, which we retrieved at our institution.The reports obtained information on early documents on the taxonomy and research work articles on Suregada since historical times as well as current reports.The obtained information from about 50 articles was carefully read, to obtain the publications meeting the aim of this work with a few older publications to reveal some necessary points.Only published work on Suregada was selected for this review.Due to the lack of human clinical trials, studies based on both in vitro and in vivo conditions were contained within the review, but, only those studies that used isolated substances.

Medicinal Uses of Suregada Species
The medicinal uses of nine of the 32 Suregada plants are presented in Table 1 and described below.
3.2.Suregada angustifolia (Müll.Arg.)Airy Shaw Suregada angustifolia (Figure 1) is ground and mixed with water to prepare the paste, then applied to the body for the treatment of skin infections.When the S. angustifolia stem bark is boiled with water and salt, it can be utilized as a mouthwash for treating toothache.Indian people in Kanis use S. angustifolia to treat skin infections and toothache [9].

Suregada lithoxyla (Pax & K.Hoffm.) Croizat
The wood of S. lithoxyla (Figure 1) is hard and used to make tool handles, spoons, firewood, and poles.The tree is suitable for ornamental purposes and is used for shade [14].
3.7.Suregada multiflora (A.Juss.)Baill. 1) is utilized to treat gum and hepatic ailments in traditional medicines [15,16].According to the report of Tewtrakul et al., S. multiflorum is mixed with other herbs and used as an anticancer recipe, while in Thailand, it is used as a traditional medicine recipe (Table 1) [17].Tewtrakul et al., further stated that the wood of S. multiflorum was used to treat pyrexia, eczema, and venereal diseases; the roots of this plant are utilized to treat skin infection and lymphatic disorders [17].In Thailand, S. multiflora is utilized to treat skin diseases including rashes, itching, and inflammation [18].In some regions, the granule products of this species can be prepared, which acts as a powerful organic herbicide [19].In India, the seeds of S. multiflora are utilized in the treatment of liver diseases and as a gum tonic [20].Suregada multiflora is harvested as timber to be used as firewood, rafters, and tool handles and cultivated as an ornamental [21][22][23].

Suregada procera (Prain) Croizat
This species is suitable for musical instruments, joinery, flooring, furniture, mine props, vehicle bodies, turnery precision equipment, interior trim, novelties, sporting goods, toys, agricultural implements, and draining boards [14].The wood of S. procera (Figure 1) is hard and is used for firewood, handles, and poles in construction.The tree can be used for ornaments and shade [14].The S. procera stem is used to treat hemorrhoids and gonorrhea.The stem of S. procera is burnt and fired in the affected area [24].
Tanzanian people used S. zanzibariensis (Figure 1) stem bark and root extract for treating ankylostomiasis.Its root extract is used to treat gonorrhea, stomachache, pneumonia, hernia, chest pains, and chicken pox, and as a purgative.The roots are drunk as an extract or chewed to treat snakebites, and Kenyan people use the roots to treat edema.Crushed leaves are ingested in porridge to expel worms and to treat dysentery.The powdered leaves are consumed in porridge or tea to treat poliomyelitis [25].In Dares Salam, S. zanzibariensis leaves are boiled in water and applied topically or douched two times a day to treat vaginal candidiasis [26].Tanzanian people mix S. zanzibariensis leaves with the Zanthoxylum chalybeum, and Acalypha fruticosa milled and scrubbed on the skin to treat skin infection [27].Giriama and Duruma people use a root decoction to treat body swelling.Digo people use the root decoction for body pains, for pains during menstruation, and to avoid premature birth [28,29].The wood of S. zanzibariensis is hard and used for tool handles, building poles, spoons, withies, and firewood.The tree is used for shade, soil conservation near the sea, and amenity.The roots are boiled, and the juice is drank twice a day as a purgative [14].
tiflora is harvested as timber to be used as firewood, rafters, and tool handles and c vated as an ornamental [21][22][23].

Suregada procera (Prain) Croizat
This species is suitable for musical instruments, joinery, flooring, furniture, m props, vehicle bodies, turnery precision equipment, interior trim, novelties, spor goods, toys, agricultural implements, and draining boards [14].The wood of S. pro (Figure 1) is hard and is used for firewood, handles, and poles in construction.The can be used for ornaments and shade [14].The S. procera stem is used to treat hemorrh and gonorrhea.The stem of S. procera is burnt and fired in the affected area [24].

Suregada zanzibariensis Baill.
Tanzanian people used S. zanzibariensis (Figure 1) stem bark and root extract for tr ing ankylostomiasis.Its root extract is used to treat gonorrhea, stomachache, pneumo hernia, chest pains, and chicken pox, and as a purgative.The roots are drunk as an ext or chewed to treat snakebites, and Kenyan people use the roots to treat edema.Crus leaves are ingested in porridge to expel worms and to treat dysentery.The powde leaves are consumed in porridge or tea to treat poliomyelitis [25].In Dares Salam, S. zibariensis leaves are boiled in water and applied topically or douched two times a da treat vaginal candidiasis [26].Tanzanian people mix S. zanzibariensis leaves with the Z thoxylum chalybeum, and Acalypha fruticosa milled and scrubbed on the skin to treat infection [27].Giriama and Duruma people use a root decoction to treat body swell Digo people use the root decoction for body pains, for pains during menstruation, an avoid premature birth [28,29].The wood of S. zanzibariensis is hard and used for tool h dles, building poles, spoons, withies, and firewood.The tree is used for shade, soil servation near the sea, and amenity.The roots are boiled, and the juice is drank twi day as a purgative [14].

Diterpenoids
Diterpenoids are a class of natural products known for their structural diversity.Diterpenoids isolated from Suregada genera belong to ent-abietane, diterpene lactone, entkuarane, and ent-pimaranes classes [36,37].Ditepenoids consist of four isoprene units which form a 20-carbon backbone.The core structures for diterpenoids are classified into macrocyclic, bicyclic, linear, tricyclic, tetracyclic, and pentacyclic types [38].Naturally, occurring diterpenoids are often found in different polyoxygenated forms with hydroxyl groups, formyl and carbonyl groups, or lactones.There are different types of diterpenoids such as ent-abiatane (1-59), ent-kaurane (60-71), etc. Ent-abietane diterpenoids were reported to exhibit a wide spectrum of biological activities such as cytotoxic, anti-microbial, anti-cancer, and anti-inflammatory [39].Ent-Abietanes with a lactone ring are classified as one of the main bioactive compounds.For example, jolkinolide B ( 35) is well-known for its anti-tumor activity [39].Ent-abietanes diterpenoids often contain an α, β-unsaturated γ-lactone ring.Some carbons of abietane diterpenoids, form a double bond or are substituted with hydroxyl or keto groups [40].The varying skeletal structures of diterpenes result from geranylgeranyl pyrophosphate (GGPP) and are classified according to their biosynthetic pathways and cyclization patterns [41].According to Dewick diterpenes start from geranylgeranyl diphosphate (GGPP), formed by the addition of an isopentenyl diphosphate (IPP) molecule to Farnesyl diphosphate (FPP) [41].Cyclization of GGPP mediated by carbocation formation, allows many structural alternatives of diterpenoids to be formed [41].Dewick further mentioned that during cyclization, the loss of diphosphate occurs which generates the first carbocation, and several natural diterpenes have been formed by varying mechanisms through cyclization [41].
The formation of carbocation formation begins by protonation of the double bond at the head of the chain, which leads to the initial cyclization sequence.Furthermore, the loss of the diphosphate later on gives rise to a carbocation and causes further cyclization.Protonation of GGPP can start a joint cyclization sequence, the loss of a proton from a methyl terminates the cyclization sequence, producing (−)-copalyl PP [41].Folding of the substrate on the enzyme surface controls the stereochemistry of (−)-copalyl PP.Nevertheless, alternate folding results in (+)-copalyl PP (labdadienyl PP), the enantiomer of (−)-copalyl PP, which has an opposite configuration at the newly produced chiral centers.From (−)-copalyl PP, several cyclizations and a rearrangement, all catalyzed by a single enzyme kaurene synthase, produce ent-kaurene [42].Formation of ent-kaurene involves the loss of the diphosphate leaving group which enables the carbocation-mediated product of the third ring system, which then forms the fourth ring [41].
Earlier the biosynthesis of ent-kaurane was described, the latter is the suggested biosynthesis of ent-abietane diterpenoid.The suggested biosynthesis of ent-abietane lactones is shown in Scheme 1 [42].Some of the ent-abietane lactones including Jolikinolide (35) may be biosynthesized from the ent-neoabietadiene.The oxidation of ent-neoabietadiene could lead to an intermediate labeled (a).Then, the intermediate (a) might be oxidized to obtain intermediate (b) and (c) [42].The highly oxidized ent-abietane diterpenoid skeleton (c) may undergo a series of intramolecular cyclization, oxidation, and dehydration reactions to produce the ent-abietane diterpenoids bearing an additional five-membered lactone ring, including 35 [42].
Earlier the biosynthesis of ent-kaurane was described, the latter is the suggested biosynthesis of ent-abietane diterpenoid.The suggested biosynthesis of ent-abietane lactones is shown in Scheme 1 [42].Some of the ent-abietane lactones including Jolikinolide (35) may be biosynthesized from the ent-neoabietadiene.The oxidation of ent-neoabietadiene could lead to an intermediate labeled (a).Then, the intermediate (a) might be oxidized to obtain intermediate (b) and (c) [42].The highly oxidized ent-abietane diterpenoid skeleton (c) may undergo a series of intramolecular cyclization, oxidation, and dehydration reactions to produce the ent-abietane diterpenoids bearing an additional five-membered lactone ring, including 35 [42].Studies conducted on Suregada indicated the presence of several types of diterpenoids.In particular, compounds 1-59, the ent-abietane diterpenoids containing an additional five-membered lactone ring, revealed important pharmacological anti-tumor and anti-inflammatory activities to name a few.The specific functional groups besides the lactone ring in these ent-abietane diterpenoids can differ depending on the compound's biosynthetic origin and its specific modifications [43].These functional groups such as hydroxyl, epoxide, acetates, ketones, and alkene collectively contribute to the compound's chemical and biological properties, making ent-abietane diterpenoids a diverse group of natural products with various potential applications in pharmacology, medicine, and Scheme 1. Suggested biosynthesis of some ent-abietane lactones including Jolkinolide B (35).Oxidation of ent-neoabietadiene led to the formation of intermediate (a).Oxidation of (a) could lead to the production of intermediate (b).Intermediate (c) was produced from a possible demethylation of (b).

Intermediate see may undergo cyclization to yield (d). Dehydration of intermediate (d) produces intermediate (e).
Studies conducted on Suregada indicated the presence of several types of diterpenoids.In particular, compounds 1-59, the ent-abietane diterpenoids containing an additional five-membered lactone ring, revealed important pharmacological anti-tumor and antiinflammatory activities to name a few.The specific functional groups besides the lactone ring in these ent-abietane diterpenoids can differ depending on the compound's biosynthetic origin and its specific modifications [43].These functional groups such as hydroxyl, epoxide, acetates, ketones, and alkene collectively contribute to the compound's chemical and biological properties, making ent-abietane diterpenoids a diverse group of natural products with various potential applications in pharmacology, medicine, and other fields of research.The biological activities of ent-abietane diterpenoids are often related to their interactions with specific molecular targets in biological systems, and the presence of particular functional groups can be crucial for these interactions [43].
Diterpenoids are named by making use of the main name of their skeletons.If the backbone of the diterpenoid comprises many functional groups namely carboxylic, aldehyde groups, lactone, or olefinic carbons, their position will be named according to the numbering of the skeleton, and the name will be followed by the suffix -oic, -al, -olide, or -en, respectively [43].The presence of hydroxyl and epoxide groups is named before the parent name.Greek letters α or β are utilized when a hydroxyl, epoxide, acetoxyl, or coumaroyl group in the compound is, respectively, upon or behind the plan of the skeleton [Sandjo, Rubinger] such as compounds 33, 36-41, etc.The location of epoxide, hydroxyl groups, and other substituents in the diterpene cores are given between the terms ent, syn, or neo and the name of the skeleton.The stereochemistry at C-9 and C-10 in the decalin part (ring A and B) of most diterpenoids can be cis or trans, depending on their orientation, and the naming syn and ent are utilized.When C-20 and C-11 are behind the compound plan, the prefix ent will follow the parent name [43].
The 1 H NMR spectrum of compound 4 (Figure 1) showed the presence of a trisubstituted cyclopropane ring.Two upfield resonances of the C-18 cyclopropane methylene protons H-18 (exo), δH −0.01, and H-18 (endo), δH 0.40 at δC 21.8, the H-3 signal at δH 0.54 at δC 19.1, and one quaternary carbon resonance (C-4, δC 16.1) confirmed the presence of a trisubstituted cyclopropane ring in ring A. Jahan further confirmed that these values aligned with the values reported for the metasequoic acids that were reported as a novel skeleton from the investigation of phytochemicals from Merasaquoia glyptostroboide [45] containing a trisubstituted cyclopropyl substituent in ring A of a labdane skeleton.Compounds 5, 6, and 7 had similar NMR signals that indicated the presence of a cyclopropane group.All these compounds were deduced to have a rearranged abietane skeleton [34].The cyclopropyl ring on the ent-abietane or ent-abietane lactones is rare.Several modified pimarane diterpenoids and tiglianes contain the cyclopropane system [45].
Kalenga reported that modified ent-abietane diterpenoids with a terminal olefinic bond at C-4, such as in compounds 58 and 59, are rare.The terminal double bond at C-4 is proposed to arise through an enzymatic 1,2-methyl shift, either of CH 3 -18 or CH 3 -19, from C-4 to C-3, followed by dehydrogenation [46].The suggested biosynthesis for compounds 58 and 59 is shown in Scheme 2 [46].The oxidation of ent-copalyl PP leads to the production of ent-pimaradiene.Then, the ent-pimaradiene could be oxidized to obtain an intermediate containing a lactone ring which is an ent-abietane diterpenoid skeleton.The ent-abietane diterpenoid skeleton may undergo a series of transformations namely, hydrogenation, and dehydrogenation, and then followed by enzymatic 1.2 methyl shift to produce compound 58 or epoxidation for compound 59 [46].The 1 H NMR spectrum of compound 4 (Figure 1) showed the presence of a trisubstituted cyclopropane ring.Two upfield resonances of the C-18 cyclopropane methylene protons H-18 (exo), δH -0.01, and H-18 (endo), δH 0.40 at δC 21.8, the H-3 signal at δH 0.54 at δC 19.1, and one quaternary carbon resonance (C-4, δC 16.1) confirmed the presence of a trisubstituted cyclopropane ring in ring A. Jahan further confirmed that these values aligned with the values reported for the metasequoic acids that were reported as a novel skeleton from the investigation of phytochemicals from Merasaquoia glyptostroboide [45] containing a trisubstituted cyclopropyl substituent in ring A of a labdane skeleton.Compounds 5, 6, and 7 had similar NMR signals that indicated the presence of a cyclopropane group.All these compounds were deduced to have a rearranged abietane skeleton [34].The cyclopropyl ring on the ent-abietane or ent-abietane lactones is rare.Several modified pimarane diterpenoids and tiglianes contain the cyclopropane system [45].Kalenga reported that modified ent-abietane diterpenoids with a terminal olefinic bond at C-4, such as in compounds 58 and 59, are rare.The terminal double bond at C-4 is proposed to arise through an enzymatic 1,2-methyl shift, either of CH3-18 or CH3-19, from C-4 to C-3, followed by dehydrogenation [46].The suggested biosynthesis for compounds 58 and 59 is shown in Scheme 2 [46].The oxidation of ent-copalyl PP leads to the production of ent-pimaradiene.Then, the ent-pimaradiene could be oxidized to obtain an intermediate containing a lactone ring which is an ent-abietane diterpenoid skeleton.The ent-abietane diterpenoid skeleton may undergo a series of transformations namely, hydrogenation, and dehydrogenation, and then followed by enzymatic 1.2 methyl shift to produce compound 58 or epoxidation for compound 59 [46].The chemical structures of the diterpenoids isolated from Suregada species are discussed below.
The chemical structures of the diterpenoids isolated from Suregada species are discussed below.

Abiatane-Type Diterpenoids
Abietanes are tricyclic diterpenoids found in nature that have been isolated from a variety of terrestrial plant sources.Araucariaceae, Cupressaceae, Phyllocladaceae, Pinaceae, and Podocarpaceae families, as well as some species from Asteraceae, Celstraceae, Hydrocharitaceae, and Lamiaceae families, and even some fungi species, are known to contain abietane diterpenoids.Abietane diterpenoids have a wide range of biological activities.Apart from the antimicrobial, antiviral, antimalarial, antiulcer, anti-leishmaniasis, and antioxidant activities reported by the scientists, they also reveal antitumor-promoting activity and antivirus properties by inhibiting the reproduction of viruses such as herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), varicella zoster virus (VZV), and Epstein-Barr virus [17,36,47].Aromatic abietanes are the most abundant abietane group.Aromatic abietanes are primarily represented by dehydroabietic acid and ferruginol.Aromatic abietanes, like most diterpenoids, are mostly known as chemical defense agents.Antimicrobial, antileishmanial, antiplasmodial, antifungal, antitumor, cytotoxicity, antiviral, antiulcer, cardiovascular, antioxidant as well and antiinflammatory activities are the biological activities of this group reported up to now.Various diterpenoids have been assigned structures that could be derived by adjusting or cleaving the abietane skeleton, known as rearranged abietane.Triptergulides A and B are novel rearranged abietane diterpenes isolated from Tripterygium wilfordii (Celastraceae), a medicinal plant used in Traditional Chinese Medicine to treat a variety of diseases including systemic lupus erythematosus, psoriasis, ankylosing spondylitis, and idiopathic IgA nephropathy.Over 59 (1-59) ent-abietane-type diterpenoids were isolated from Suregada species which remains the abundant diterpenoids from the genus.

Pharmacological Activities of the Suregada Genus
The reviewed published article revealed that some of the isolated phytochemicals were tested for their pharmacological activities while some were not evaluated.Suregada species and some phytochemicals were screened for their antileishmanial, antidiabetic, antioxidant, cytotoxic, anti-plasmodial, antimicrobial, and anticancer activity.A summary of some Suregada species activities is presented in Table 2.
Aqueous, chloroform, and ethanol extracts of S. angustifolia bark and leaves were screened against two bacterial strains (Gram-positive and negative) and two fungal strains using the disc diffusion method.The aqueous leaf extract revealed zone inhibition of Pseudomonas aeruginosa (18.00 mm) and Bacillus subtillis (8.00 mm).The aqueous extract of S. angustifolia bark revealed zone inhibition of P. aeruginosa (20.00 mm) and B. subtillis (15.00 mm).The chloroform bark extract showed antibacterial properties against P. aeruginosa and B. subtilis with zone inhibition values of 18.00 mm and 15.00 mm.The ethanol leaf

Pharmacological Activities of the Suregada Genus
The reviewed published article revealed that some of the isolated phytochemicals were tested for their pharmacological activities while some were not evaluated.Suregada species and some phytochemicals were screened for their antileishmanial, antidiabetic, antioxidant, cytotoxic, anti-plasmodial, antimicrobial, and anticancer activity.A summary of some Suregada species activities is presented in Table 2.
Aqueous, chloroform, and ethanol extracts of S. angustifolia bark and leaves were screened against two bacterial strains (Gram-positive and negative) and two fungal strains using the disc diffusion method.The aqueous leaf extract revealed zone inhibition of Pseudomonas aeruginosa (18.00 mm) and Bacillus subtillis (8.00 mm).The aqueous extract of S. angustifolia bark revealed zone inhibition of P. aeruginosa (20.00 mm) and B. subtillis (15.00 mm).The chloroform bark extract showed antibacterial properties against P. aeruginosa and B. subtilis with zone inhibition values of 18.00 mm and 15.00 mm.The ethanol leaf extract revealed activity against P. aeruginosa, S. aureus, and B. subtilis with zone inhibition values of 9.00 mm, 20.00 mm, and 12.00 mm, respectively [25].
The antibacterial activity of S. multiflorum leaves, bark, and stem extracts was investigated.The leaves hexane extracts revealed partial zone inhibition against Mycobacterium lacticola and S. aureus (10 to 11 mm).The hexane extract of S. multiflorum bark showed zone inhibition of 10 mm against S. aureus.The leaf dichloromethane extracts partially showed zone inhibition of 10 mm against S. aureus, 0.5 mm against E. coli, and 11 mm against M. lacticola and moderately revealed zone inhibition of 16 mm Bacillus subtilis [60].The bark dichloromethane extracts showed a moderate zone inhibition of 12 to 13 mm, 15 mm, 13 to 14 mm, and 12 to 13 mm against S. aureus, B. subtilis, M. lacticola, and Xanthomonas campestris, respectively.The stem hexane extract revealed partial inhibition against M. lacticola with a zone inhibition value of 11 mm.The stem-dichloromethane extracts showed partial zone inhibition of 0.3 mm against E. coli and 3 mm against X. campestris and moderate inhibition against S. aureus, B. subtilis, and M. lacticola with zone inhibition of 13 mm, 13 mm and 18 mm, respectively [60].The dichloromethane extract was the most active extract, followed by hexane and methanol extracts [60].

Antifungal Activity
Jahan et al. stated that Suregadolide A (4) isolated from S. multiflora revealed an antifungal effect of minimum concentration that produces zone inhibition of 12 mm diameter (IC 12 ) of 70 and 35 µg•mL −1 in the RAD+ and RAD52 mutant yeast assays, respectively [34].

Antidiabetic Activity
The water extract of S. glomerulata leaves revealed an inhibitory effect against αglucosidase with the IC 50 2.29 µg•mL −1 [53].

Cytotoxicity
The dichloromethane-methanol crude extract of S. multiflorum revealed promising cytotoxicity against 60-cell tumour panels conducted at the NCI [16].According to Kigondua et al., the ethyl acetate extract of S. multiflorum stem was cytotoxic against the cancer cell (MDA-MB435) [74].Ethanol extract of the S. multiflorum bark revealed cytotoxicity against cervical cancer (Hela cells).The leaves aqueous and methanol extracts of S. zanziberiensis revealed low toxicity towards human embryonic lung fibroblast (HELF) cells with a 50% cytotoxic concentration (CC 50 ) of >20 µg•mL −1 [74].

Methanol extracts
Possessed good anti-leishmanial activity on Leishmania major amastigotes with a mortality percentage of 28.0 ± 2.11%.
Revealed substantial differences in the production of NO by macrophages infected with Leishmania major amastigotes (6.6 ± 0.63 µM).

Aqueous extracts
Showed a significant difference in the production of nitric oxide by macrophages infected with Leishmania major amastigotes (4.0 ± 0.56 µM).

In vitro cytotoxicity
Low toxicity was observed against HELF cells with a cytotoxic concentration of 50% (CC 50 ) value > 20 µg•mL −1 .

Comparison of Ethnomedicinal Uses with the Pharmacological Uses
Several plant species of the Suregada genus are utilized by locals in traditional medicine against various ailments such as headaches and colds, dysentery, malaria, placenta apposition, epilepsy, skin diseases, worms, weakness, blood vomiting, piles, toothache, eczema, venereal diseases, pyrexia, lymphatic disorders, hepatitis, fungal infection, leprosy, fever, poisonous effects, stomach disorder, squint eye, gum disease, asthma, dysentery, vaginal candidiasis, abdominal pains, wound healing and ankylostomiasis and also as purgative, an astringent and against snakebite.Pharmacological studies were conducted on various species of this genus, such as anti-inflammatory, anticancer, antiviral, antidiabetic, antimicrobial, antileishmanial, antiplasmodial, cytotoxic, antioxidant, and insecticidal activity.A comparison of traditional medicinal uses of genus Suregada with the pharmacological studies is described as follows:

•
The methanol and hexane extracts of S. anguistifolia, showed a maximum antibacterial effect against E. coli, A. hydrophila, and K. pneumonia.A similar activity was observed in S. aureus in chloroform and methanol extracts of S. anguistifolia stem bark.Staphylococcus aureus bacteria cause toothache and skin infections [9].The pharmacological results from this plant species support the claims of traditional medicinal uses of S. anguistifolia, where Indian people in Kanis utilize it to treat skin infections and toothache [9].

•
The wood of S. multiflora was reported to treat pyrexia, eczema, and venereal diseases, and the roots are utilized to treat lymphatic disorders and skin infections [17].In Thailand, S. multiflora is utilized to treat skin diseases and inflammation [17].Various solvent extracts from S. multliflora were screened for antibacterial and antimicrobial activity and exhibited effects against B. subtilis, P. aeruginosa, Shi.flexineri, S. aureus, and E. coli [62].S. aureus is responsible for skin infections, gum diseases, eczema, and pyrexia (fever).The bacteria P. aeruginosa is responsible for lymphatic disorders, which can include swelling.E. coli and shi.flexineri responsible for pyrexia (fever) [76].Helioscopinolide A (1) and epifriedelinol (75) isolated from S. multiflora revealed antibacterial activity that further substantiates the traditional uses claims of S. multiflora.Epifriedelinol (75) exhibited the highest zone inhibition against S. aureus.S. aureus is the bacteria responsible for skin infection, eczema, and gum diseases [57,59,71].Suregadolide (4) isolated from S. multiflora showed antifungal activity, which confirms the claims of the traditional uses of the plant being utilized for treating fungal infections and skin disease [34].

•
In some regions, the granule products of this species can be prepared, which acts as a powerful organic herbicide [19].When tested for insecticidal activity, the (1:9) methanol: ethyl acetate root extract of S. multiflora revealed a mortality rate of 100% for Tribolium castaneum at 50 mg•mL −1 dose in 12 h [61].Furthermore, the dichloromethane extract of S. multiflora stem showed partial antibacterial activity with zone inhibition of 3 mm against X. campestris [55].S. multiflora revealed an antibacterial activity against X. campestris, which is responsible for plant diseases and insecticidal activity, which confirms the claims that the granules of S. multiflora act as organic herbicide [55,78].

•
A mixture of S. multiflorum is mixed with other herbs it is used as an anticancer recipe [17].Helioscopinolide A (5) and gelomulide E (12) isolated from S. multiflora showed anticancer activity against various types of cancer, namely, leukemia (CCRF CEM), leukemia (SR), leukemia (K-562), breast (MD-MB-435), and colon (HTC-15) which supports the claims of S. multiflora being used traditionally in the anticancer recipe.• S. zanzibariensis leaves are utilized to treat malaria.The leaf extract of S. zanzibariensis revealed high anti-plasmodial activity with the IC 50 value of1.5 µg•mL −1 ) against Plasmodium falciparum K67 and ENT36 [77].

•
Giriama and Duruma people use a root decoction to treat body swelling [28].Tanzanian people used the stem bark and root extract of S. zanzibariensis to treat ankylostomiasis caused by parasitic hookworms [25].Nitrogen production macrophages infected with amastigotes of Leishmania major treated with the methanol and aqueous extracts of S. zanzibariensis showed significant Nitric oxide concentration at 4.0 ± 0.56 and 6.6 ± 0.63 µg•mL −1 at 1000 µg•mL −1 [74].The potent activity of this species against Leishmania, a parasitic disease, supports the claim that S. zanzibariensis is used to treat ankylostomiasis and body swelling.Simiarenol (81) isolated from S. zanzibariensis exhibited noticeable antinociceptive properties with the ID 50 of 18.87 (14.6-24.4)mmol•kg −1 [71,72].The activity of Simiarenol validates the claims of S. zanziberiensis being traditionally used for chest and abdominal pains.

Conclusions
The objective of this review was to outline the previous findings on the genus Suregada focusing on phytochemicals, pharmacological activities, and medicinal uses of the extracts and phytochemicals isolated from Suregada the species.The results showed that the genus Suregada is important due to its traditional medicinal benefits.This genus contains compounds that could be further explored for treating various ailments.
The Suregada species are traditionally utilized in treating gum and hepatic diseases, mixed with other herbs, and used as an anticancer recipe to treat pyrexia, eczema, venereal diseases, lymphatic disorder, skin infection, skin infections, toothache, ankylostomiasis, gonorrhea, and stomach-ache.Pharmacological studies revealed that the compounds in the Suregada species exhibit diverse biological activity, including antibacterial, antimicrobial, antiplasmodial, anticancer, and antiviral as in Figure 13.The presence of biologically active tested phytochemicals in Suregada species could afford an important basis in the discovery of drugs.Moreover, most of the activities investigated so far are in vitro testing, and no in vivo screenings were performed.The biochemical interaction through which the extracts and isolated compounds of Suregada produce its pharmacological effects of displaying promising activities should be further investigated.

Funding:
The authors would like to thank the South African National Research Foundation (NRF) for the funding.The research for which this review article is supported by the NRF Thuthuka Grants UID: 117898 (Dr.V.J. Tembu) and UID: 117872 (Prof.C. Tarirai).

Not applicable
Data Availability Statement: Data sharing is not applicable.

Conflicts of Interest:
The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this paper.A significant number of investigations have been conducted on S. multiflora and S. zanzibariensis; nevertheless, other species have not been widely investigated.Suregada species, mainly.S. multiflora and S. zanzibariensis are utilized traditionally in the treatment of various illnesses.S. zanzibariensis root extract is drunk to treat gonorrhea, stomachache, pneumonia, hernia, chest pains, chicken pox, and as a purgative.There is a need for further evaluation of this species since the relationship between traditional and pharmacological uses is not clearly shown.The antimicrobial studies for S. zanzibariensis should be performed to substantiate the mentioned claims.Furthermore, S. zanzibariensis is traditionally used to treat vaginal candidiasis, which may be yeast or fungal infection; conducting antifungal candida studies to substantiate the claims is needed.Suregada multiflorum is traditionally used to treat venereal diseases and hepatitis.The antiviral activity of these plants and their phytochemicals should be studied.Future pharmacological and phytochemical investigations of African Suregada species should focus on other traditionally used and accepted species, such as S. procera, which is used to treat hemorrhoids and gonorrhea.The other six African species are accepted species, but their traditional uses are not known, namely, S. africana, S. croizatiana, S. gossweileri, S. ivorense, S. lithoxylia, and S. occidentale.Other Suregada species (S. decidua, S. boiviniana, and S. adenophora) have known traditional uses but have not been investigated for their pharmacological uses and phytochemistry.

Lists of Abbreviations
The presence of biologically active tested phytochemicals in Suregada species could afford an important basis in the discovery of drugs.Moreover, most of the activities investigated so far are in vitro testing, and no in vivo screenings were performed.The biochemical interaction through which the extracts and isolated compounds of Suregada produce its pharmacological effects of displaying promising activities should be further investigated.

Figure 2 .
Figure 2. Representation of different metabolites in genus Suregada.

Scheme 1 .
Scheme 1. Suggested biosynthesis of some ent-abietane lactones including Jolkinolide B (35).Oxidation of ent-neoabietadiene led to the formation of intermediate (a).Oxidation of (a) could lead to the production of intermediate (b).Intermediate (c) was produced from a possible demethylation of (b).Intermediate see may undergo cyclization to yield (d). Dehydration of intermediate (d) produces intermediate (e).

Pharmaceuticals 2023 ,
16,  x FOR PEER REVIEW 26 of 30 traditional uses but have not been investigated for their pharmacological uses and phytochemistry.

Figure 13 .
Figure 13.Summary of the ethnomedicinal, phytochemistry, and pharmacological properties of Suregada species.

Table 1 .
Some reported ethnomedicinal uses of Suregada species.
Structures of fatty alcohol, steroidal glycoside, and phytosterols isolated from S. angustifolia.

Table 2 .
Pharmacological activities of the Suregada genus.