plants Systematic Review The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora Adriana Ribeiro, Rita Serrano , Isabel B. Moreira da Silva, Elsa T. Gomes, João F. Pinto and Olga Silva * Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal; ribeiroadriana@edu.ulisboa.pt (A.R.); rserrano@edu.ulisboa.pt (R.S.); isabelsilva@edu.ulisboa.pt (I.B.M.d.S.); eteixeiragomes@sapo.pt (E.T.G.); jfpinto@ff.ul.pt (J.F.P.) * Correspondence: osilva@edu.ulisboa.pt; Tel.: +351-217-946-400 Abstract: Species of the Diospyros L. genus (Ebenaceae family) have been largely used in traditional medicine for the treatment of several diseases, especially infectious ones. To date, active major compounds such as naphthoquinones, triterpenoids, and tannins have been isolated and pharmacologically validated from Diospyros species. The present study summarizes the information available in the literature on the species described in the Flora of Mozambique. To do so, scientific databases (e.g., PubMed, Scopus, Web of Science, and Google Scholar) were searched using various keywords and Boolean connectors to gather and summarize the information. Of the 31 native and naturalized species in the Flora of Mozambique, 17 are used in different regions of Africa and were described for their traditional uses. They were reported to treat more than 20 diseases, mostly infectious, in the gastrointestinal and oral cavity compartments. This work provides an overview of the therapeutical potential of Diospyros species and explores novel insights on the antimicrobial potential of extracts and/or isolated compounds of these Mozambican species. Keywords: antimicrobial activity; anti-inflammatory activity; cytotoxicity; Diospyros; ethnomedicinal practice; herbal medicine; infectious diseases Citation: Ribeiro, A.; Serrano, R.; da Silva, I.B.M.; Gomes, E.T.; Pinto, J.F.; Silva, O. The Genus 1. Introduction Diospyros: A Review of Novel The genus Diospyros L. (Ebenaceae family) contains species that have been recognized and used in traditional medicine (extended ethnomedical use) and have potential new health benefits supported by in vitro biological, in vivo pharmacological, and clinical tests [1–4]. Furthermore, within certain cultures or communities, various traditional systems have used all plant parts of this botanical genus (leaf, fruit, bark, twig, hardwood, and root) as herbal medicines [1,4]. Beyond their pharmacological value, Diospyros spp. have distinct and complementary important qualities, namely valuable wood, and edible fruits, which provide significant economic benefits and are recognized and utilized in various industrial and commercial sectors [1,4]. Generally, Diospyros spp. are tree shrubs or subshrubs with entire alternate leaves, solitary flowers, and fleshy fruits (berries) with usually two or more seeds. The characteristics of the leaves and flowers of these species are often used to identify fossil casts [5–7]. Diospyros species are predominantly distributed between the tropics, and the most notable diversity of this botanical genus occurs in Africa [5,6,8]. As confirmed in The Plant List [9], the WFO Plant List currently contains 1575 species related to the genus Diospyros, of which 734 have accepted scientific names [10]. Regarding the Mozambican flora, the genus is represented by 31 species (Table 1), corresponding to 18 accepted scientific name species, seven accepted subspecies (subsp.), three species that are considered synonyms, and three species that are not yet in the WFO plant list as of 12 February 2022 [10–12]. Insights into the Biological Activity and Species of Mozambican Flora. Plants 2023, 12, 2833. https:// doi.org/10.3390/plants12152833 Academic Editor: Adeyemi Oladapo Aremu Received: 26 June 2023 Revised: 21 July 2023 Accepted: 29 July 2023 Published: 31 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Plants 2023, 12, 2833. https://doi.org/10.3390/plants12152833 https://www.mdpi.com/journal/plants Plants 2023, 12, 2833 2 of 34 Table 1. Species of the genus Diospyros L. present in Mozambican Flora. First Discription Year 1980 Scientific Name Author Common Name English/Local MD 1 N Z T MS GI M CD Np IUCN 2 D. anitae F.White malawi star apple/- LC 1911 D. bussei Gürke coral star-berry/- NT 1935 D. consolatae Chiov. -/novolo LC 1963 D. dichrophylla (Gand.) De Winter poison star-apple/- LC 1933 D. ferrea (Willd.) Bakh. -/- A coastal jackal-berry/dodo LC 1962 D. inhacaensis F.White 1988 D. kabuyeana F.White -/- LC large-leaved jackal-berry/ cula, fuma, jacualala, mucula, murriba, tendje LC NT 1873 D. kirkii Hiern 1980 D. mafiensis F.White -/- 1844 D. mespiliformis Hochst. ex A.DC. african ebony, jackal-berry/ muribariba, mucula, muquéué, murriparipa, mutona, mussuma 1956 D. quiloensis (Hiern) F.White crocodile-bark jackal-berry/ midodo, murodo 1873 D. rotundifolia Hiern dune star-apple/ impapa, mapiti, munhentze 1861 D. senensis Klotzsch spiny jackal-berry/ matamba, mudalima, tombatica LC LC ∇ LC LC ∆ NE 1861 D. squarrosa Klotzsch rigid starberry/cachenz’ere, mpomopo, senzasicana, sicana 1980 D. truncatifolia Caveney square-leaved star apple/ impope, mpope LC LC 1873 D. verrucosa Hiern warty star-apple/djacola, mkonhomo, nkalanongo, riparipa 1961 D. whyteana (Hiern) P.White bladder-nut/- LC 1963 D. zombensis (B.L.Burtt) F.White malawi star-apple/- LC 1891 D. abyssinica subsp. abyssinica (Hiern) F.White giant diospyros/- LC 1988 D. abyssinica subsp. attenuata * (Hiern) F.White giant diospyros/- LC 1980 D. abyssinica subsp. chapmaniorum (Hiern) F.White giant diospyros/- LC 1837 D. loureiriana subsp. loureiriana a G.Don dye star-apple, sand starapple/chipongoti, nhandima LC 1805 D. lycioides Desf. subsp. sericea (Bernh.) De Winter eastern blue-bush, red star-apple/ chitomatomana, m’dima LC Plants 2023, 12, 2833 3 of 34 Table 1. Cont. First Discription Year Scientific Name Author Common Name English/Local 1968 D. natalensis subsp. natalensis * (Harv.) Brenan acorn jackal-berry/- A 2009 D. natalensis subsp. nummularia (Harv.) Brenan Jordaan acorn diospyros, acorn jackal-berry, granite jackal-berry **/- A F.White -/aboba, kidanko, mpome, nhamudima, popa LC A b D. usambarensis subsp. usambarensis /rufescens MD 1 N Z T MS GI M CD Np IUCN 2 c D. villosa (L.) var. villosa De Winter hairy starapple/nhachibabane, nhaurratane, chicanela, chicumbela, chibabane c D. villosa var. parvifolia (De Winter) De Winter hairy star-apple/- A - - A d D. consolatae-rotundifolia intermediates d D. kirkii-mespiliformis intermediates - - A d D. sp. no. 1 sensu FZ - - A 1 Distribution in Mozambique (blue, MD) [10,11]; Common name local (green, MD) [12]: N—Niassa; Z—Zambezia; T—Tete; MS—Manica and Sofala; GI—Gaza–Inhambane; M—Maputo; CD—Cabo Delgado; Np—Nampula; * Not identified; ** Other names—small-leaved jackal berry, Tickey tree; ∇: Gaza; ∆: Sofala. 2 International Union for the Conservation of Nature: LC—least concern; NE—not evaluated; NT—near threatened [B2ab(iii)]; A—absent. WFO Plant List: a D. loureiroana G.Don subsp. loureiriana; b Synonym of D. loureiroana subsp. rufescens (Caveney) Verdc.; c Synonym of D. villosa (L.) De Winter; d not included in the WFO Plant List [10,11]; (-)—not available. Concerning primary health care (PHC), herbal medicines are used by 80% of the African population, and more than 70% of the population of Mozambique uses such medicines for treating all diseases [13–15]. For instance, several Diospyros species with antimicrobial potential have been reported [4,16–18]. Worldwide, the magnitude of infectious diseases (ID), encompassing antimicrobial resistance (AMR), represents a major health problem (approximately 700,000 people die every year) [19,20]. Infectious diseases have a high impact in Africa, particularly in Mozambique [21]. Most of the native and naturalized Diospyros species of Mozambique’s flora are generally recognized as traditionally used in different regions of Africa to treat different diseases, with a particular focus on infections affecting the gastrointestinal tract and oral cavity. This work will present a comprehensive overview of the therapeutic potential of Mozambican Diospyros species based on chemical, biological, and toxicological experimental data, particularly addressing its antimicrobial properties and including comparative elements concerning the biological activity of other Diospyros species. 2. Results 2.1. Ethnomedical Use of Diospyros Species of Mozambican Flora Table 2 shows the results of the collected ethnomedical data from seventeen Mozambican species, namely D. abyssinica, D. anitae, D. ferrea, D. kabuyeana, D. loureiriana subsp. loureiriana, D. lycioides subsp. sericea, D. mafiensis, D. mespiliformis, D. rotundifolia, D. mafiensis, D. mespiliformis, D. quiloensis, D. rotundifolia, D. squarrosa, D. usambarensis, D. verrucosa, D. villosa, D. villosa var. parvifolia, D. whyteana, and D. zombensis. In addition, information is given on the part of the plant used as medicine, the manufacturing process of the traditional formulation, the main traditional therapeutic use, and the country from which the information originates. Plants 2023, 12, 2833 4 of 34 The results show that 54.8% of the total Diospyros species from Mozambique are referred to for their traditional use (Table 2). Among these, D. rotundifolia (Figure 1), traditionally used to treat diarrhea [22], is a prevailing species of dense undergrowth in the coastal area of the Marracuene District [23]. Figure 1. Diospyros rotundifolia: (a) aspect in its natural habitat; (b,c) details of leaf and fruit; (d) transverse view of the fruit with the seeds. Photography by Elsa Gomes. Furthermore, among the Diospyros species present in the Mozambican flora, D. villosa (Figure 2) is a species with a well-established traditional use of both leaf [24] and root [25]; the latter mainly used as a toothbrush for hygiene purposes [26]. Plants 2023, 12, 2833 5 of 34 tt Figure 2. Diospyros villosa: (a) Aspect in the natural habitat; (b) cross-section of the root. Photography by Elsa Gomes (a) and Adriana Ribeiro (b). Diospyros species have been reported to be used to treat the signals and symptoms of over 20 diseases. Two of these species (D. abyssinica and D. mespiliformis) have been mentioned most frequently and are used in two to fiveffdifferent countries in Africa (Table 2). ff Based on the diverse description in the literature for the human use of the different parts of Diospyros, the results are grouped into infectious diseases (antibacterial, antifungal, anthelminthic, and antiviral); gastrointestinal (diarrhea, dysentery, emetic, flatulence, and other gastrointestinal disorders), oral cavity (oral hygiene, healing of oral wounds, and toothaches); urogenital (anti-hemorrhagic, dysmenorrhea, and infertility); skin diseases (dermatitis, fresh wounds, bedsores, and rashes); musculoskeletal (body pain, bruises, painful fractures, and rheumatism); and others conditions (diabetes, internal injuries, antidotes, hemostatic agents, and snake bites). tt Among all the different Diospyros plant parts used in traditional medicine (Figure 3), ff ff the root is the most-used part (82%, Figure 3a) and is most used to treat infectious diseases. In the treatment of gastrointestinal disorders, it corresponds to 59%, for oral cavity infections, 41%, and for skin diseases, 18%, as well as for the management of other conditions, comprising 12% (Figure 3b). Figure 3. Traditional use of Diospyros species: (a) plant part used; (b) type of disease. Plants 2023, 12, 2833 6 of 34 The leaf is the second-most used part of the Diospyros species, but it is used in a similar percentage (18%) to the root to treat skin conditions and more commonly (24%) for musculoskeletal bruises, painful fractures, body aches, and rheumatism (Figure 3a,b). Table 2. Reported ethnomedical use of Mozambican Diospyros species. Species Part Used Preparation Method leaf decoction fruit (dry) decoction bark unspecified root decoction leaf bark juice bark decoction leaf seed squeeze and apply leaf juice tuber decoction root unspecified fruit unspecified root Traditional Use Country Ref. Mali [4,27] Mali, Guinea Zimbabwe [28] Kenya [29] D. abyssinica malaria wound healing astringent and cholagogue gastrointestinal disorders astringent and antipyretic antihelminthic abdominal pain, dysentery, and diarrhea snake bite astringent internal injuries laxative rash malaria and ringworm ringworm wound healing tropical ulcer (skin and soft tissue polymicrobial infection, feet, or lower legs localized) upset stomach [30] Uganda [31] [32] D. anitae dental hygiene healing of oral wounds Mozambique [33] India [34] unspecified diarrhea and sore throats internal bleeding renal lithiasis anti-hemorrhagic infertility oral hygiene skin diseases unspecified antiviral Tanzania [37] chewing stick oral hygiene South Africa East Africa [4] decoction bloody feces South Africa South Central Zimbabwe [38–40] Namibia Zambia [41] D. ferrea bark [35,36] D. kabuyeana root D. loureiroana subsp. loureiroana root D. lycioides subsp. sericea root bark dysentery headache root chewing stick infertility Plants 2023, 12, 2833 7 of 34 Table 2. Cont. Species Part Used Preparation Method Traditional Use Country Ref. root unspecified diarrhea Mozambique Tanzania [42] Central Southern Eastern Western Africa [27,43–47] Burkina Faso [48] Ghana [27] Nigeria [49–51] Zambia [44,52] D. mafiensis leprosy skin diseases (including fungal infections) D. mespiliformis leaf and bark decoction leaf decoction root leaf, bark and root chewing stick analgesic and antipyretic antihelminthic dermatomycosis fungal infections induction of childbirth hemostatic agent malaria, pneumonia, and trypanosomiasis sexually transmitted diseases diarrhea and dysentery leprosy oral infections whooping cough bruises, bedsores, rash, and wounds ringworm oral hygiene decoction toothache leaf decoction antipyretic dermatitis diarrhea and dysentery malaria headache pneumonia rheumatism malaria and pneumonia infection with fever antipyretic antidote for a variety of poisonous substances diarrhea and dysentery haemostatic agent oral infections wound healing malaria and oral candida infection (used as mouthwash, management of HIV/AIDS opportunistic diseases) leaf decoction fruit decoction stem bark root leaf decoction decoction decoction root decoction root infusion abdominal pain, body and heart pain seed unspecified antibacterial stem bark decoction malaria sexually transmitted diseases Zambia [44] root not report diarrhea South African [22] root not report sexually transmitted diseases Tanzania [37] South Central Zimbabwe Guinea [53] [4] D. quiloensis D. rotundifolia D. squarrosa Plants 2023, 12, 2833 8 of 34 Table 2. Cont. Species Part Used Preparation Method root bark root unspecified chewing stick Traditional Use Country Ref. schistosomiasis oral hygiene fungal infections and overt symptoms of type 2 diabetes (i.e., polyuria, polydipsia, excessive thirst, and sweating) Malawi Tanzania [54] [55,56] leprosy Tanzania [4,57] South African [24] Mozambique [4,25,58] South Africa [59] D. usambarensis decoction D. verrucosa root unspecified leaf unspecified D. villosa decoction root toothbrush decoction D. villosa var. parvifolia leaf gastrointestinal disorders painful fractures gastrointestinal disorders laxative musculoskeletal system oral hygiene wounds (skin/subcutaneous tissue) emetic antihelminthic emetic and flatulence gastrointestinal disorders infusion root D. whyteana root unspecified antibacterial dysmenorrhea rash South Africa [60] root bark unspecified schistosomiasis Malawi [4,61] D. zombensis The majority of documented medicinal uses of Diospyros species are attributed to their effectiveness in treating microbial infections, encompassing bacterial, fungal, and parasitic infections. These include conditions such as diarrhea, dysentery, and various skin and oral cavity infections. 2.2. Chemical Composition of Mozambican Diospyros Species The main classes of chemical constituents identified in Diospyros species from the Mozambican flora are listed in Table 3. The presence of phenolic acid derivatives, like flavonoids and naphthoquinones (NQs), particularly 1,4-naphthoquinones (1,4-NQs), and terpenoids, mainly triterpenoids (especially lupan, ursane, oleanane derivatives) [3,4,17,62,63] and tetraterpenoids (carotenoids), have been reported [4]. Other chemical constituents in these Diospyros species include hydrocarbons, lipids, amino acids, and sugars [1,4,5,62]. Table 3. Chemical compounds identified in Mozambican Diospyros species. Species Part Used Chemical Class root bark naphthoquinone stem bark leaf naphthoquinone triterpenoid Compounds Extract Ref. plumbagin (2-methyl-5-hydroxy-1,4-naphthoquinone) diospyrin, isodiospyrin betulinic acid, betulin and lupeol P. ether, CF, DCM, MeOH, H2 O, EtOH 80% MeOH [28] D. abyssinica [64,65] Plants 2023, 12, 2833 9 of 34 Table 3. Cont. Species Part Used Chemical Class Compounds Extract Ref. n.r n.r triterpenoid naphthoquinone betulinic acid, betulin and lupeol diosindigo A n.r n.r [4] [4] seed naphthoquinone isodiospyrin Hex [66] MeOH n.r MeOH MeOH EtOAc [67] [4] [67] EtOAc [67] n-Hex [68] n-Hex [68] CF, n-Hex [68,69] EtOH [70] EtOH [4] n.r [4] D. consolatae D. dichrophylla D. ferrea leaf n.r leaf leaf diterpenoid leaf triterpenoid fruit triterpenoid fruit root fruit root triterpenoid naphthoquinone leaf triterpenoid n.r triterpenoid pregnenolone and androstan-6-one β-sitosterol citronellol phytol thunbergol betulin, α-amyrin, friedelan-3-one and olen-12-ene friedelin, epifriedelinol, lupeol, lupenone, and betulin β-sitosterol and stigmasterol 7-methyljuglone, isodiospyrin, diosindigo A and 8-hydroxyisodiospyrin gallic acid friedelin, friedelin-3-ol, taraxerol and taraxerone ursolic acid stem naphthoquinone 7-methyljuglone and diospyrin n.r [71] n.r n.r n.r triterpenoid bauerenol, betulin and lupeol β-sitosterol diosindigo A n.r n.r n.r [4] [4] [4] branche fruit root, stem naphthalene naphthoquinone triterpenoid naphthoquinone naphthoquinone MeOH MeOH n.r n.r CF [72] [41] [53] [71] [71] n.r naphthoquinone Diospyroside A, B, C and D 7-methyljuglone and juglone lupeol and ursolic acid isodiospyrin and bisisodiospyrin 7-methyljuglone and isodiospyrin mamegakinone, methylnaphthazarin and 8-hydroxyisodiospyrin n.r [4] root bark naphthoquinone CF, DCM, MeOH [42,73,74] stem bark leaf bark naphthoquinone triterpenoid naphthoquinone stem bark triterpenoid diosquinone, diosindigo A, 7-methyljuglone, 3-hydroxiquinone, and 6,8-bisdiosquinone 7-methyljuglone and diosindigo A α-amyrin, lupeol and betulinic acid diosquinone, isodiospyrin, and plumbagin lupeol, betulin, betulinic acid, α-amyrin, and bauerenol triterpenoid monoterpenoid phenol [67] D. inhacaensis D. kirkii naphthoquinone D. lycioides D. mafiensis CF, MeOH Ee [73] [75] [4,52] CF [4,76] Plants 2023, 12, 2833 10 of 34 Table 3. Cont. Species Part Used Chemical Class Compounds Extract Ref. stem bark, leaf, bark triterpenoid betulinic acid, betulin, lupeol, bauerenol, and α-amyrin CF, MeOH [4,76] n.r [77] P. ether MeOH MeOH [78] [79] [79] D. mespiliformis leaf flavonoid root root, bark fruit naphthoquinone naphthoquinone naphthoquinone 7-O-(4′′′ -O-acetyl)-allopyranosyl(1′′′ → 2′′ )β-glucopyranoside, along with eight flavonoid metabolites—luteolin 3′ ,4′ ,6,8-tetramethyl ether, luteolin 4′ -O-β-neohesperidoside, luteolin 7-O-β-glucoside, luteolin, quercetin, quercetin 3-O-β-glucoside, quercetin 3-O-α-rhamnoside, and rutin diosquinone, and plumbagin diospyrin plumbagin root, stem n.r n.r naphthoquinone triterpenoid fatty acid 7-methyljuglone, and diospyrin betulinic acid, α-amyrin, and lupeol heptacosanoic acid n.r n.r n.r [4] [4] [4] n.r naphthalene 4,5,6,8-tetramethoxy naphthaldhyde, 5-hydroxy-4,6,8-trimethoxy naphthaldehyde, 4,5,6-trimethoxynaphthalehyde, 4,5-dimethoxynaphthaldehyde, and 5-hydroxy-4-methoxy-2-naphthaldehyde MeOH [4] n.r triterpenoid root naphthoquinone stem D. natalensis D. quiloensis D. rotundifolia n.r [4] n.r [71] naphthoquinone betulin and lupeol 7-methyljuglone, neodiospyrin and rotundiquinone 7-methyljuglone and diospyrin n.r [71] n.r naphthoquinone 7-methyljuglone n.r [4] root naphthoquinone MeOH [54,80] stem bark naphthoquinone MeOH [54] root bark naphthoquinone n.r [57] root bark triterpenoid stem bark naphthoquinone n.r [57] stem bark triterpenoid diosindigo A, 7-methyljuglone, diosquinone and isodiospyrin betulinic acid and betulin diosindigo A, 7-methyljuglone, diosquinone and isodiospyrin betulinic acid and betulin n.r [57] n.r naphthoquinone 7-methyljuglone n.r [4] bark triterpenoid MeOH [4] root bark naphthoquinone oleanolic acid 7-methyljuglone, diosquinone, isodiospyrin and mamegakinona P. ether, MeOH [4,61] D. squarrosa D. usambarensis 7-methyljuglone, isodiospyrin, diosindigo A and B, bis-isodiospyrin and mamegakinone 7-methyljuglone and diosindigo A D. verrucosa D. whyteana D. zombensis Extract: Ace—acetone; CF—chloroform; DCM—dichloromethane; Ee—ether; EtOAc—ethyl acetate; EtOH—ethanol; H2 O—water; Hex—hexane; MeOH—methanol; P. ether—petroleum ether; n.r—not reported. Plants 2023, 12, 2833 11 of 34 Among the NQs (Figure 4), 80% are 1,4-NQs, either as monomers such as plumbagin (1) and 7-methyljuglone (2) or as dimers such as diospyrin (3) and isodiospyrin (4), while trimers and tetramers are less represented in this genus [4,81]. Figure 4. Diospyros representatives identified 1,4-naphthoquinones. In the Mozambican Diospyros species, plumbagin (1) and 7-methyljuglone (2) are the most prominent 1,4-NQs identified [3,4]. The presence of 7-methyljuglone has been reported in diethyl ether, dichloromethane, chloroform, methanol, and hydroethanol extracts of the root, stem, and bark of most species [1,5] and in the ether extract of D. lycioides branches [41]. Plumbagin has been identified on the root bark of D. abyssinica [28], and isodiospyrin (4), a dimeric 7-methyljuglone derivative [3], has been reported in a hexane extract of D. dichrophylla seeds [66] and in the diethyl ether extract of bark and phylum of almost all Mozambican Diospyros species [4]. D. mespiliformis has been one of the best-studied Mozambican Diospyros species, having NQs identified in different plant parts [4,79] and triterpenoids in leaf, bark, and stem bark [4,76,82]. ff Triterpenoids (lupane, ursane, oleanane, taraxerane, and friedelane) are present in more than 90% of Diospyros species. Lupane-type compounds (Figure 5), such as betulinic acid (1, Figure 5), betulin (2, Figure 5), and lupeol (3, Figure 5), are the most active substances present in Diospyros African species [4,64,83,84]. These compounds were detected in different types of extracts (petroleum ether, dichloromethane, chloroform, methanol, hydroethanol, and aqueous extracts) and their fractions [1,5,28,41]. Several biological activities ff have been demonstrated for them, mainly for betulinic acid and its derivatives [83,85–88]. Condensed tannins (proanthocyanidins and oligopolymeric complex tannins), and particularly hydrolysable tannins (gallotannins, ellagitannins), and have also been identified in Mozambican Diospyros species such as D. villosa [4,25,58] and D. mespiliformis [82,89]. In addition, from the methanolic extract derived from D. lycioides twigs, three naphthalene glycosides were identified [72], and carotenoids were identified in the fruit of this species [90]. The presence of galactiol and vitamin E in the D. ferrea leaf was also reported [67]. Plants 2023, 12, 2833 12 of 34 Figure 5. Diospyros identified representative lupan-type triterpenoids. So far, the biologically active marker secondary metabolites isolated and studied from several species of the genus Diospyros have mainly been naphthoquinones, triterpenoids, and tannins. Compounds belonging to these chemical classes have been isolated from the twigs, bark, roots, leaves, stems, and fruits of Mozambican species of this genus. Examples include plumbagin, 7-methyljuglone, diospyrin, and isodiospyrin, which have been isolated from the root of several Diospyros species. 2.3. In Vitro and In Vivo Biological Activity of Mozambican Diospyros Species and Marker Compounds In Tables 4–6, the different in vitro and in vivo biological activities and toxicological tests performed on Mozambican Diospyros species, and their isolated marker secondary metabolites are summarized. A total of thirteen species (41.9%), namely D. abyssinica, D. bussei, D. ferrea, D. kabuyeana, D. lycioides, D. loureiriana, D. mafiensis, D. mespiliformis, D. natalensis, D. squarrosa, D. usambarensis, D. verrucosa, and D. villosa, were evaluated for biological activities other than antibacterial activities (Table 4). 2.3.1. Anti-Inflammatory and Analgesic Activity Aqueous extract of D. abyssinica root bark has shown stronger anti-inflammatory activity (enzyme 15-lipoxygenase (LOX) inhibition) than quercetin [27]. ff that the hexane fraction of D. mespiliformis leaves has antiIn vivo assays have shown inflammatory properties (inhibits stronger the LOX), and that the methanolic extracts of different plant parts showed wound healing effects. On the other hand, the butanol and ethyl acetate fractions activate LOX activity. These results show that D. mespiliformis extract can have pro-inflammatory and anti-inflammatory effects [51]. Lupeol isolated from D. mespiliformis stem bark has shown analgesic activity in both pain inhibition (neurological-first phase) and origin (inflammatory-second phase) in biphasic tests (in vivo) [76]. 2.3.2. Antihyperglycemic Activity Another finding has revealed that the oral administration of a methanolic extract obtained from the leaves of D. ferrea (400 mg/kg) for a duration of 21 days in diabetic rats ffshowed significant antihyperglycemic activity ff [91]. The root of this species is rich in phenolic acids, especially gallic acid, and is therefore traditionally used as a potent antioxidant [70]. ff 2.3.3. Antifungal Activity Several studies have reported the potential antifungal activity of the root and root bark of most Diospyros species [42,54,92]. However, the antifungal activity of a leaf extract of D. mespiliformis has also been confirmed [47,93]. Various Diospyros medicinal plants are also effective against Candida spp. [1]. The methanolic extract of the D. abyssinica root is active against this microorganism [94]; how- Plants 2023, 12, 2833 13 of 34 ever, in another study, it was only moderately active against the same microorganism [95]. Another medicinal plant, D. mespiliformis, is more active against C. neoformans than against C. albicans. A leaf extract showed anti-C. albicans activity, while a bark extract showed in vitro activity against C. neoformans-isolated strains from South African AIDS patients [96]. D. mespiliformis, traditionally used to treat ringworm, shows remarkable antimicrobial activity against Trichophyton mentagrophytes and Microsporum canis. This result supports the traditional use of this species against dermatophytosis [47]. Aqueous and ethanolic extracts of the leaf and bark of D. mespiliformis showed significant antifungal activity against Aspergillus niger, Aspergillus flavus, and Microsporum gypseum [97]. 2.3.4. Antiparasitic Activity Diospyros species have antiparasitic activity, especially against both chloroquinesensitive (3D7) and chloroquine-resistant (FcB1) strains of Plasmodium falciparum [31,94]. The decoction of the stem of D. mespiliformis was tested against Plasmodium bergheiinfected mice and demonstrated potent activity, including the inhibition of beta-hematin in an in vitro study [98]. In vitro studies from methanolic extracts of D. abyssinica leaves have provided confirmation of its antiparasitic activity against Leishmania donovani [65,94], Trypanosoma cruzi, Trypanosoma brucei [99], Culex, and Anopheles larvae [94]. The isolated compound 7-methyljuglone obtained from the methanolic extract of D. usambarensis root bark has significant schistosomicidal activity [54,92]. 2.3.5. Antioxidant Activity The scavenging activity of crude extract and fractions of four Diospyros species, namely D. abyssinica, D. lycioides, D. mespiliformis, and D. villosa, present in the Mozambican Flora was evaluated spectrophotometrically using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical assay. An estimation of the concentration of antioxidant vitamins (i.e., A, C, and E) from crude methanolic extracts obtained from the leaf, bark, and root of D. mespiliformis was also determined using the DPPH [51]. Table 4. In vitro and in vivo non-antibacterial tests of biological activity in Mozambican species of Diospyros and marker compounds. Biological Activity/ Species PU Extract/ Compound Results Microorganism/ Assay Control Ref. Biphasic, Wistar rats acetylsalicylic acid (asa), 100 mg/kg, p.o. [76] Tail flick method, adult Wistar albino rats ibuprofen [100] Tail flick method, adult Wistar albino rats ibuprofen [101] Analgesic D. mespiliformis SB D. ferrea L D. ferrea R CF/lupeol 25 mg/kg, p.o CF MeOH CF MeOH Pi1 2.2 ± 0.2/ asa =1.0 ± 0.3 Pi2 1.98 ± 0.1/ asa =1.15 ± 0.1 100–300 mg/Kg significant activity 100–200 mg/Kg significant activity Anti-inflammatory D. abyssinica Rb D. ferrea L D. ferrea R D. mespiliformis H2 O (1) MeOH (2) CF MeOH CF MeOH 1—IC50 = 16 ± 1 µg/mL 2—IC50 = 86 ± 7 µg/mL 100–300 mg/Kg = 26.2–28.2% 100–300 mg/Kg = 29.6–37.6% 100–200 mg/Kg = 37% Sb DCM Fraction maximally at 400 mg/kg Modulation of serum concentrations of Tumour Necrosis Factor alpha and Interleukin 1 beta and 6 L Hex Fraction 5 µg/mL(1) 10 µg/mL (2) 1—IC50 = 31.21 ± 0.84 µg/mL 2—IC50 = 32.05 ± 2.79 µg/mL LOX, using soybean lipoxygenase type 1-B PIPE, adult male Wistar rats PIPE, adult Wistar albino rats quercetin, IC50 value 11.5 ± 0.6 µg/mL ibuprofen 41.1% [27] [100] ibuprofen [101] Cytokine inhibition, Plasmodium berghei-infected mice artemetherlumefantrine [98] LOX, Wistar rats quercetin, IC50 value 1–46.02 ± 5.46 µg/mL 2–32.05 ± 2.79 µg/mL [51] Plants 2023, 12, 2833 14 of 34 Table 4. Cont. Biological Activity/ Species PU Extract/ Compound Results Microorganism/ Assay Control Ref. L MeOH 21 days 400 mg/kg, i.p, significant antihyperglycemic activity Streptozotocin induced diabetic Wistar rats glibenclamide, 0.5 mg/Kg, p.o. [91] D. abyssinica R MeOH Actives in test controlled by conidial suspension BA, C. albicans C. cucumerinum methylthiazolyltetrazolium [94] chloride (MTT) D. ferrea W 1-isodiospyrin 2-plumbagin 1—active against three fungi 2—active against eight fungi HMBC Phomopsis sp. reference spectrum for both H1 and C13 [102] D. mafiensis Rb 3-hydroxydiosquinone 3-hydroxydiosquinone MIC50 = 14.9 µg/mL MIC50 = 39.1 µg/mL Reduced total aflatoxin, 1.145 to 32 ng/plac A. parasiticus B62 [42] A. parasiticus B62 [42] Rb diosquinone MIC50 > 100 µg/mL A. parasiticus B62 [42] Rb diosquinone Reduced total aflatoxin 1.145 to 45 ng/plac A. parasiticus B62 [42] Rb P. ether, DCM (E) Fraction (F) E = 5 mg/disc IZ: 7–20 mm F = 0.2 mg/disc IZ: 19–20 mm DD, C. albicans miconazole 20 µg/disc IZ: 29 mm [103] Rb L Ace MIC = 0.16 µg/mL BD, C. albicans, M. canis amphotericin B MIC = 0.02 µg/mL [93] L DCM:MeOH MIC = 0.10–0.50 mg/mL BD, M. canis, T. mentagrophytes tetrazolium violet [47] [93] [96] Antihyperglycemic D. ferrea Antifungal Rb D. mespiliformis CCA, A. f lavus, A. parasiticus ELISA, A. parasiticus, A. flavus CCA, A. flavus, A. parasiticus ELISA, A. flavus, A. parasiticus H2 O MIC = 0.08 µg/mL BD, M. canis amphotericin B MIC = 0.02 µg/mL B Ace IZ: 7 mm (1) IZ: 12 mm (2) ADD, 1-C. albicans, 2-C. neoformans nystatin Rb 7methyljuglone MIC = 0.025 µg/mL Rb isodiospyrin MIC = 10 µg/mL D. villosa R EtOH 70% Fraction MIC = 312.5 µg/mL MIC = 62.5–312.5 µg/mL BD, C. albicans not reported [104] Antiparasitic D. abyssinica L EtOAc IC50 = 51.3 ± 8.8 µg/mL IC50 = 1.5 µg/mL IC50 = 5.6 µg/mL BD, P. falciparum (FcB1) L. donovani P. falciparum chloroquine pentamidine chloroquine pentamidine IC50 = 7 µM chloroquine IC50 = 0.1 µM [31] L D. usambarensis B B B R EtOAc BA, C. cucumerinum BA, C. cucumerinum miconazole MIC = 0.001 µg/mL miconazole MIC = 0.001 µg/mL [92] [54] [65] diospyrin isodiospyrin diospyrin isodiospyrin DCM MeOH IC50 = 0.5 µM L. donovani IC50 = 1.5 µM P. falciparum (FcB1) MIC = 500 mg/L Culex, Anopheles larvae not identified [94] [94] [94] D. bussei R MeOH IC50 = 65.7 ± 2.7 µg/mL T. brucei (Lister 427) pentamidine IC50 = 0.000509 µM [99] D. kabuyeana L MeOH IC50 = 3.32 µg/mL T. brucei (Lister 427) pentamidine IC50 = 0.000509 µM [99] D. loureiriana Rb Sb L MeOH IC50 = 1.68 ± 0.77 µg/mL IC50 = 11.53 ± 1.99 µg/mL IC50 = 19.10 ± 4.41 µg/mL P. falciparum (3D7) chloroquine IC50 = 0. 0045 µM [105] [105] [105] D. mespiliformis S EtoAC (1) DCM (2) MeOHfraction (3) 1—IC50 = 3.18 µg/mL 2—IC50 = 0.78 µg/mL 3—IC50 = 0.55 µg/mL Plasmodium berghei-infected mice artesunate and chloroquine diphosphate [98] D. natalensis Sb MeOH IC50 = 2.85 µg/mL T. brucei (Lister 427) pentamidine IC50 = 0.000509 µM [99] D. squarrosa Rb MeOH IC50 = 5.38 µg/mL T. brucei (Lister 427) pentamidine IC50 = 0.000509 µM [99] Plants 2023, 12, 2833 15 of 34 Table 4. Cont. Biological Activity/ Species PU Extract/ Compound Results Microorganism/ Assay Control Ref. Sb R L MeOH MeOH MeOH IC50 = 1.28 µg/mL IC50 = 2.23 µg/mL IC50 = 2.99 µg/mL T. brucei (Lister 427) T. brucei (Lister 427) T. brucei (Lister 427) pentamidine IC50 = 0.000509 µM [99] Rb 7methyljuglone Efficiency schistosomiasis MIC = 5 ppm Biomphalaria glabrata not identified [54] D. abyssinica Rb EtOH (1) MeOH (2) H2 O (3) 1-EC50 = 16.0 ± 2 µg/mL 2-EC50 = 16.6 ± 0.4 µg/mL 3-EC50 = 21 and 29 ± 2 µg/mL DPPH quercetin EC50 value 3.4 ± 0.3 µg/mL [27] D. lycioides L Ace Rf = 0.54; 0.60; 0.83; 0.89 DPPH on TLC plates phenolic compounds [38] D. mespiliformis F R F MeOH MeOH MeOH 87.36% at 1 mg/mL IC50 = 3.47 ± 0.05 µg/mL IC50 = 6.94 ± 0.49 µg/mL DPPH DPPH DPPH B MeOH IC50 = 7.82 ± 0.76 µg/mL DPPH L EtOAc Fraction IC50 = 1.08 ± 0.04 µg/ml DPPH Sb MeOH IC50 = 9.53 µg/mL DPPH L CF (1) Hex (2) 1-IC50 = 10.7 µg/mL 2-IC50 = 11.8 µg/mL DPPH D. verrucosa D. usambarensis Antioxidant D. villosa vitamin E ascorbic acid 2.36 ± 0.30 µg/mL trolox 3.43 ± 0.78 µg/mL ascorbic acid 5.08 ± 0.12 µg/mL ascorbic acid 10.3 µg/mL ascorbic acid 10.3 µg/mL [106] [51] [51] [51] [51] [107] [107] Part used (PU): L—leaf; B—bark; F—fruit; R—root; Rb—root bark; Sb—stem bark. Extract: Ace—acetone; ADD—agar disc diffusion; CF—chloroform; DCM—dichloromethane; EtOAc—ethyl acetate; EtOH—ethanol; H2 O—water; Hex—hexane; MeOH—methanol; P. ether—petroleum ether. Test: BA—TLC bioautography; BD—broth dilution; CCA—cell culture in agar; DD: disco diffusion method; DPPH—2,2-diphenyl-1picrylhydrazyl; ELISA—enzyme-linked immunosorbent assay; HMBC—heteronuclear multiple-bond correlation method; PIPE—percent inhibition of paw edema. Abbreviations: LOX-15-lipoxygenase; Pi1 —pain inhibition (neurological-first phase); Pi2 —pain inhibition (inflammatory-second phase); EC50—half maximal effective concentration; IC50—half maximal inhibitory concentration; MIC—minimum inhibitory concentration. 2.3.6. Cytotoxicity, Genotoxicity, and Toxicity of Mozambican Diospyros Species The results of in vitro cytotoxicity tests using normal and tumorous human cells and Artemia salina, as well as in vitro genotoxicity and in vivo acute and sub-chronic toxicity assessment of Diospyros species, are summarized in Table 5. Table 5. In vitro cytotoxicity and genotoxicity studies as well as in vivo toxicity studies in Mozambican Diospyros species. Species Parts Used Extract leaf EtOAc Toxicity Assay Results Ref. IC50 = 6.0 ± 5.0 µg/mL [31] D. abyssinica leaf EtOAc bark EtOAc seed DCM:MeOH (1) isodiospyrin (2) Cytotoxicity against MRC-5 human diploid embryonic cells, Taxotere® as standard Cytotoxicity against KB human tumor cell lines (squamous cell carcinoma of the mouth), Taxotere® as standard Cytotoxicity against human KB cell (1) and Rhabditis pseudoelongata (2) >85% cell inhibition IC50 = 1.0 ± 2.0 µg/mL [31] (1) LD50 = 10 µg/mL (2) LD50 = 1 µg/mL [65] Cytotoxicity using Brine shrimp test (Artemia salina) 1-(LC50 = 29 µg/mL) 2-(LC50 = 0.13 µg/mL) [66] D. dichhropylla Plants 2023, 12, 2833 16 of 34 Table 5. Cont. Species Parts Used Extract Toxicity Assay Results Ref. leaf MeOH In vivo—acute oral toxicity using male Wistar albino rats LD50 = 2000 mg/kg [91] fruit isodiospyrin (1) 8′ -hydroxyisodiospyrin (2) Cytotoxicity strong against Hep-3B, KB, COLO-205, and HeLa cancer cells 1(ED50 = 0.17, 1.72, 0.16 and 0.21 µg/mL) 2(ED50 = 1.31, 1.75, 1.96 and 1.79 µg/mL) [68] IC50 = 500 and 1000 µg/mL [38] Nontoxic to the normal cell at 300 µg/mL [38] IC50 = 100.34 ± 9.85 µg/mL [105] IC50 = 57.26 ± 0.53 µg/mL [105] [103] D. ferrea D. lycioides leaf Ace leaf Ace Cytotoxicity against BUD-8 cell (human fibroblast cells) in real-time xCELLigence system and 7.4 µg/mL curcumin (control) Cytotoxicity against HeLa cells mobility assayed using the wound healing assay and 7.4 µg/mL curcumin (control) D. loureiriana root bark MeOH stem bark Cytotoxicity against human embryonic kidney cells (HEK293), estimated growth inhibition at 400 µg/ml D. mafiensis root bark P. ether (1) DCM (2) EtOH (3) fraction P. ether (4) fraction DCM (5) Cytotoxicity using brine shrimp larvae test (Artemia salina) Standard cyclophosphamide LC50 value of 17.78 µg/mL 1-LC50 2-LC50 3-LC50 4-LC50 5-LC50 EtOH In vivo—acute oral toxicity using Wistar rats of both sexes in vivo—acute oral administration using rats In vivo—sub-chronic toxicity using rats Cytotoxicity against human glioblastoma cell lines (1) and hormone-dependent human prostate cancer (2) LD50 = 570 mg/kg Acute toxicity is moderate [49] LD50 ≥ 5 g/kg [108,109] LD50 = 750 g/kg LD50 = 500 g/kg [108] 1-ED50 = 0.18 µg/mL 2-ED50 = 4.50 µg/mL [84] = 25.12 µg/mL = 69.18 µg/mL = 120.23 µg/mL ≤ 8–45.71 µg/mL = 5.08 µg/mL D. mespiliformis stem bark root bark leaf stem bark leaf stem bark EtOAc fraction root diosquinone twigs DCM Genotoxicity against mutagens mitomycin C (MMC) using the Ames test (Salmonella typhimurium TA98) protective effect non-genotoxic at 500–2500 µg/mL [60] leaf DCM HydroMeOH 90% Genotoxicity using the Ames test (Salmonella typhimurium TA98) shift mutations of lowest dose is 0.50 µg/mL higher doses are toxic [110] root HydroEtOH 70% In vivo—acute toxicity using mice possible renal dysfunction development [58] root bark 7-methyljuglone (1) isodiospyrin (2) Cytotoxicity against human colon carcinoma cells 1-LD50 of 7.0 × 10−2 µg/mL 2-LD50 of 3.8 × 10−2 µg/mL [61] MeOH D. whyteana D. villosa D. zombensis Extracts: Ace—acetone; DCM—dichloromethane; EtOAc—ethyl acetate; EtOH—ethanol; H2 O—water; Hex—hexane; HydroEtOH—ethanol; HydroMeOH—methanol; MeOH—methanol; P. ether—petroleum ether. Concentration: ED50 —median effective dose; IC50 —half maximal inhibitory concentration; LC50 —lethal concentration 50%, LD50 —lethal dose 50%. Plants 2023, 12, 2833 17 of 34 Most commonly, studies were found to be related to the in vitro assessment of cytotoxicity. For example, the extract of D. lycioides showed cytotoxicity to HeLa cells but was non-toxic to normal cells [38]. The compound diosquinone has been shown to be toxic against most cancer cell lines (human glioblastoma) and hormone-dependent human prostate cancer [84]. In contrast, 7-methyljuglone and isodiospyrin compounds are active against human colon carcinoma cells [61]. The organic extract of the inner seed of D. dichrophylla (Figure 6) is reported as highly cytotoxic (LC50 = 29 µg/mL), particularly the isodiospyrin isolated from it (LC50 = 0.13 µg/mL) [66]. Figure 6. Diospyros dichrophylla (Gand.) De Winter: Detail of fruits in nature, Mandevo, Namaacha district, Maputo, 2010. Photography by Elsa Gomes. Preclinical safety assessments of Diospyros species are of paramount importance; however, few studies related to Mozambican Diospyros species have been conducted to date. Cantrell et al. (2003) reported that D. dichrophylla is a potent phytotoxicant due to the presence of isodiospyrin (from the inner seed) at a lethal dose of 0.13 g/mL [66]. In another study, a hydroethanolic root extract of D. villosa showed possible development of renal dysfunction using an acute toxicity test in mice [111]. 2.3.7. Antibacterial Activity In vitro antibacterial activity data collected from eleven Diospyros species (representing 35.5% of the total) are summarized in Table 6. Of the 11 species examined, 47 extracts (including AgNPs) showed antimicrobial activity against multiple bacterial strains. The methanolic extract was the most tested. In some of the studies mentioned, biodirected / fractionation was also performed, and the antibacterial activity of the obtained fractions and isolated compounds was determined. The results obtained are also shown in Table 6. Plants 2023, 12, 2833 18 of 34 Table 6. In vitro antibacterial activity of Mozambican Diospyros and marker compounds. Species Parts Used Test Extract/ Compound MIC (µg/mL) Microorganism Control (MIC) µg/mL Ref. bark BD EtOAc 12 S. aureus ATCC 6538 DMSO [65] leaf stem bark BD MeOH 125 E. coli ATCC 8740 ciprofloxacin 0.63 leaf BD MeOH 8000 root bark BD MeOH 500 S. aureus ATCC 25923 B. cereus ATCC 11775 E. coli ATCC 8740 ciprofloxacin 2.5 ciprofloxacin 0.08 ciprofloxacin 0.63 leaf leaf stem bark leaf stem bark BD BD BD MeOH MeOH MeOH 8000 4000 1000 BD MeOH 125 branche BD MeOH 1250 branche BD Diospyroside A branche BD Diospyroside B branche BD Diospyroside C branche BD Diospyroside D branche BD juglone branche BD 7-methyljuglone leaf BA leaf BA leaf BA EtOAc Ace EtOAc Ace MeOH EtOAc Ace MeOH D. abyssinica D. bussei [99] D. kabuyeana S. aureus ATCC 25923 ciprofloxacin 2.5 B. cereus ATCC 11775 ciprofloxacin 0.08 E. coli ATCC 8740 ciprofloxacin 0.63 [99] D. lycioides 39 78–1250 39–78 156–625 39–156 312–625 156–312 19–78 39 39–156 78 0.10–0.16 * 0.12–0.17 * 0.16–0.36 * 0.20–0.45 * 0.16–0.27 * 0.05–0.45 * 0.05–0.45 * 0.05–0.45 * S. sanguis, P. gingivalis, S. mutans, P. intermedia S. sanguis, P. intermedia P. gingivalis, S. mutans S. sanguis, P. gingivalis P. intermedia, S. mutans P. intermedia, S. mutans P. gingivalis, S, sanguis S. mutans, P. intermedia, P. gingivalis, S. sanguis P. intermedia, S. mutans, S. sanguis, P. gingivalis P. gingivalis, S. mutans S. sanguis, P. intermedia P. aeruginosa ATCC 27853 S. aureus ATCC 29213 p-iodonitrotetrazolium chloride E. faecalis ATCC 29212 p-iodonitrotetrazolium chloride alkaloid sanguinarine [41] alkaloid sanguinarine [41] alkaloid sanguinarine [41] alkaloid sanguinarine [41] alkaloid sanguinarine [41] alkaloid sanguinarine [41] alkaloid sanguinarine [41] p-iodonitrotetrazolium chloride [38] [38] [38] D. mafiensis root bark DCM S. aureus B. anthracis IZ: 12 mm root bark P. ether-Fraction IZ: 10–15 mm S. typhi, S. boydii, E. coli, K. pneumoniae S. aureus, V. cholerae Proteus sp., B. anthracis S. typhi, S. boydii, E. coli, K. pneumoniae S. aureus, V. cholerae Proteus sp., B. anthracis gentamycin ampicillin (20 µg/disc) [103] gentamycin ampicillin (20 µg/disc) [103] isoniazid 5.0 isoniazid 5.0 [50] [50] ciprofloxacin, cefixime, and gentamicin [95] D. mespiliformis leaf root ADD ADD MeOH MeOH 167 250 leaf BD EtOH 12,500–25,000 BD Hex (F1) nBOH (F2) EtOAc (F3) H2 O (F4) leaf leaf root (1)78.125–312.5 (2)156.25 (3)78.125– 156.25 (4)625–2500 625 625 (1) >2500 (2 to 4) S. aureus S. aureus Salmonella spp., Shigella spp., Campylobacter spp. 1-P. aeroginosa 2-S. aureus 3-E. coli 4-S. typhimurium gentamicin 19.53 gentamicin 19.53 gentamicin 19.53 gentamicin 19.53 [97] Plants 2023, 12, 2833 19 of 34 Table 6. Cont. Species Parts Used leaf leaf root Test AD BD AD Extract/ Compound H2 O HydroMeOH 10% H2 O HydroMeOH 10% H2 O HydroMeOH 10% H2 O HydroMeOH 10% H2 O HydroMeOH 10% flavonol O-rhamnoside MIC (µg/mL) Microorganism Control (MIC) µg/mL 250–500 125–500 H. influenzae (6 ci) ampicillin 0.12–15.6 125–250 62.5–125 S. aureus (5 ci) ampicillin 0.06–0.12 250–250 125–125 S. pneumoniae (3 ci) ampicillin 0.015–0.12 250–250 125–125 S. pyogenes (8 ci) ampicillin 0.015–0.06 250–500 125–250 M. catarrhalis (5 ci) ampicillin 0.12–1.9 9770 S. aureus not identified diosquinone 3–30 diosquinone 15–16 S. aureus NCT 6571 S. aureus E3T E. coli KL16 P. aeruginosa NCT 6750 ampicillin 5 Ref. [112] [77] [78] gentamicin 2 leaf DD methylated flavone IZ: 34 mm E. coli not identified [78] leaf AWD EtOH-Fraction IZ: 20 mm IZ: 18 mm IZ: 16 mm S. aureus, Shigella spp. P. aeruginosa septrin 15 mm spetrin 16 mm spetrin 15 mm [113] BD MeOH MeOH MeOH MeOH MeOH 250 1000 500 1000 250 S. aureus ATCC 25923 B. cereus ATCC 11775 E. coli ATCC 8740 E. coli ATCC 8740 E. coli ATCC 8740 ciprofloxacin 0.08 ciprofloxacin 2.5 ciprofloxacin 0.63 ciprofloxacin 0.63 ciprofloxacin 0.63 [99] Ace 230–1770 S. aureus, E. faecalis, E. coli and P. aeruginosa not reported [22] MeOH MeOH MeOH MeOH MeOH 4000 250 1000 4000 500 B. cereus ATCC 11775 E. coli ATCC 8740 S. aureus ATCC 25923 B. cereus ATCC 11775 E. coli ATCC 8740 ciprofloxacin 2.5 ciprofloxacin 0.63 ciprofloxacin 0.08 ciprofloxacin 2.5 ciprofloxacin 0.63 [99] D. natalensis leaf leaf leaf root bark stem bark D. rotundifolia not reported D. squarrosa leaf BD root bark BD stem bark BD leaf BD MeOH MeOH MeOH 1000 2000 500 S. aureus ATCC 25923 B. cereus ATCC 11775 E. coli ATCC 8740 ciprofloxacin 0.08 ciprofloxacin 2.5 ciprofloxacin 0.63 [99] root bark stem bark BD MeOH <6.25 E. coli ATCC 8740 ciprofloxacin 0.63 [82] D. verrucosa Plants 2023, 12, 2833 20 of 34 Table 6. Cont. Species Test Extract/ Compound MIC (µg/mL) Microorganism root BD HydroEtOH 70% Ee Fractions 62.5–312.5 15.6–62.5 31.2–62.5 E. faecalis ATCC 435628 E. coli ATCC 25922 M. luteus ATCC 10240 S. aureus ATCC 25923 leaf DD AgNPs IZ: 15 mm E. coli ATCC 25922 AgNPs 80 ◦ C IZ: 18 mm S. aureus ATCC 700698 AgNPs IZ: 16 mm AgNPs IZ: 16 mm Ace MeOH 0.05–0.45 * 0.05–0.45 * Parts Used Control (MIC) µg/mL Ref. D. villosa S. epidermidis ATCC 12228 not reported not reported not reported not reported ciprofloxacin 37 mm gentamicin 20 mm ciprofloxacin 6 mm gentamicin 11 mm [104] [107] ciprofloxacin 28 mm gentamicin 20 Test: BD—broth dilution; DD—disc diffusion; ADD—agar disc diffusion; AWD—agar well diffusion. Extract: Ace—acetone; DCM—dichloromethane; Ee—ether; EtOAc—ethyl acetate; EtOH—ethanol; H2 O—water; Hex—hexane; HydroMeOH—methanol; nBOH—n-butanol; P. ether—petroleum ether. Strains: B. anthracis— Bacillus anthracis; B. cereus—Bacillus cereus; E. faecalis—Enterococcus faecalis; H. influenzae—Haemophilus influenzae; K. pneumoniae—Klebsiella pneumoniae; M. catarrhalis—Moraxella catarrhalis; M. luteus—Micrococcus luteus; P. gingivalis—Porphyromonas gingivalis; P. intermedia—Prevotella intermedia; S. typhi—Salmonella typhi; S. typhimurium—Salmonella typhimurium; S. boydii—Shigella boydii; S. epidermis—Staphylococcus epidermidis; S. sanguis—Streptococcus sanguinis; S. mutans—Streptococcus mutans; S. pyogenes—Streptococcus pyogenes; V. cholerae—Vibrio cholerae. Abbreviations: ATCC—American type culture collection, BA—TLC bioautography, ci—clinical isolate; IZ—zone of inhibition; MIC—minimum inhibitory concentration; AgNPs—silver nanoparticles; * Rf—retardation factor. According to the WHO, oral diseases are the most common non-communicable diseases, affecting people throughout life and causing pain, discomfort, disfigurement, and even death [114]. The Global Burden of Disease Study reports that oral diseases are among the leading causes of health problems, estimating that half of the world’s population is affected by these diseases [114,115]. The same study provided a comprehensive assessment, and among the results evaluated, permanent tooth decay was the most common cause, representing a major public health problem in many countries [116]. Therefore, preventing and controlling the spread of this health problem is a global challenge, requiring greater efforts and potentially innovative approaches to achieve it. The branches of several Diospyros (particularly D. lycioides, D mespiliformis, and D. villosa) are used as toothbrushes for oral care [41,44,52,104,117], and their plant extracts have been shown to be effective against common oral pathogens, including Streptococcus mutans, S. sanguis, periodontal pathogens (Porphyromonas gingivalis and Prevotella intermedia), Lactobacillus spp., and several strains of Candida spp. [41,44,52,104,117]. In fact, over the past few decades, the scientific community has become increasingly interested in understanding the versatility of medicinal plants from traditional herbal medicine and their guaranteed availability to improve clinical approaches to infectious diseases with the intention of reducing antimicrobial resistance [4]. 2.4. Secondary Metabolites of Mozambican Diospyros Species as Potential Antimicrobial Agents 2.4.1. Naphtoquinones Antibacterial Activity Plumbagin (1, Figure 4) is recognized as an effective antibacterial agent against both Gram-positive and Gram-negative strains of bacteria. This compound has also shown significant inhibitory activity (MIC < 12.5 µg/mL) against the resistant strain of Mycobacterium tuberculosis H37Rv [3,78,118]. Plumbagin isolated from the bark extract of D. maritima and showed activity against S. aureus and Aeromonas hydrophila (MIC = 0.625 and 5 µg/mL, respectively) [119]. In addition, it has also been obtained from the root of D. mespiliformis and has been described as one of the active marker compounds as well as an effective antibacterial agent against Gram-positive and Gram-negative bacterial strains [50,77,112]. Plants 2023, 12, 2833 21 of 34 Another important compound isolated from D. hebecarpa, 7-methyljuglone (2, Figure 4), also present in the root of Euclea natalensis (Ebenaceae), is potentially active against Mycobacterium tuberculosis (H37Rv) [18]. Isodiospyrin (4, Figure 4), a dimeric 7-methyljuglone-derivative, has been reported to be more active than diospyrin (3, Figure 4) against various Gram-positive strains, including Streptococcus pyogenes, S. pneumoniae, Corynebacterium diphtheriae, Bacillus subtilis, Listeria monocytogenes, Mycobacterium chelonae, and Micrococcus luteus. Isodiospyrin demonstrates MIC values ranging from (0.78 to 50 µg/mL), while diospyrin shows MIC values ranging from (1.56 to 100 µg/mL) [17]. Extensive research has unveiled the mechanism of action of diospyrin and 7-methyljuglone against M. tuberculosis, highlighting their crucial role as non-competitive ATPase inhibitors in key enzymatic reactions [120]. Additionally, emerging evidence has demonstrated the anti-tuberculosis potential of other compounds, such as crassiflorone and plumbagin from D. crassiflora, as well as diospyrone and plumbagin from D. canaliculata, both derived from the stem bark [121]. In a study conducted by Kuete et al. (2010), it was demonstrated that isobavacalcone and diospirone, derived from D. canaliculata, show promise as potential drugs against multidrug-resistant Gram-negative strains. These compounds exhibited enhanced activity when used in combination with efflux pump inhibitors, resulting in MIC values decreased to <10 µg/mL [122,123]. Antifungal and Antiviral Activities The NQs have been well established, particularly against several species of Candida, infectious fungi of the mucosa, deep tissues, and the most common fungal diseases in HIV/AIDS patients [124]. Plumbagin inhibits the growth of C. albicans, C. tropicalis, and other fungi. In addition, fractions derived from plumbagin of Diospyros extracts are active against C. albicans [1]. In comparison with ketoconazole, a standard antifungal compound, plumbagin is considered a promising antifungal agent and has been used against C. albicans, C. glabrata, C. krusei, C. tropicalis, Cryptococcus neoformans, Aspergillus niger, A. flavus, Alternaria sp., Cladosporium sp., Geotrichum candidum, Fusarium sp., Helminthosporum sp., M. gypseum, and Penicillium sp. [125–127]. This compound, isolated from the stem bark of D. bipindensis, also exhibits significant activity against C. albicans [128–130]. Isolated from the root of D. virginiana, 7-methyljuglone and isodiospyrin have significant antifungal activity against Phomopsis obscurans (leaf blight), with 97.0% and 81.4% growth inhibition at 30 µM, respectively. These compounds also demonstrate activity against the pathogen Phomopsis viticola, with growth inhibition rates of 53.4% and 57.7%, respectively [131]. The antiaflatoxigenic activity of D. mafiensis root, another Mozambican medicinal plant, has been linked to the presence of diosquione and 3-hydroxydioquinone, making this herbal drug also an important natural antifungal for preventing fungal growth and aflatoxin accumulation in food [42]. In addition, this species has also been found to have analgesic, antidiabetic, anti-inflammatory, and antioxidant effects, likely correlated with the presence of these kind of constituents. Antiparasitic Activity NQs are highly active against pathogens in neglected tropical diseases, including malaria, leishmaniasis, and trypanosomiasis (sleeping sickness). Studies examining Plasmodium sp. have shown that isodiospyrin-derived isodiospyrol A exhibits antimalarial activity (IC50 = 2.7 µg/mL) [132]. Anti-plasmodial activity has also been reported in the ethanolic extract of leafs of D. monbuttensis (IC50 = 3.2 nM) [133]. Studies on malaria have proposed a redox cycling mechanism (described for the novel antimalarial–antiparasitic drug atovaquone) to support the in vitro activity of diospyrin and its analogues isolated from D. montana against L. donovani [134]. Plants 2023, 12, 2833 22 of 34 Plumbagin and its derivative was shown to be active against Leishmania spp., while diospyrin was active against Leishmania donovani [87]. Semisynthetic crassiflorone derivatives display trypanocidal activity against T. brucei and T. cruzi [135]. Antiplasmodial activities with IC50 values of 16.5 to 29.4 g/mL against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum were observed for the juglone-based 1,4-NQs present in D. sylvatica [136]. Concerning the assessment of anthelmintic activity, it was demonstrated in vitro that D. oocarpa, D. nigrisence, D. candolleana, and D. montana are active on adult earthworms of Pheritima posthuma [137]. Similarly, NQ derivatives, including diospyrin from D. oocarpa, D. nigrisence, and D. candolleana, are antiprotozoal in addition to possessing anthelmintic constituents [138]. 2.4.2. Triterpenoids Antibacterial and Antifungal Activities Betulinic acid isolated from the root of D. lotus presents a broad spectrum against several Gram-positive and Gram-negative bacteria [85,139–141]. Betulin isolated from D. rubra is an active agent against Streptococcus pyogenes, with a MIC of 85 µg/mL, and Corynebacterium diphtheriae, with a MIC range of 64 to 256 µg/mL [88]. Methanolic extract obtained from D. peregrina bark and seed containing triterpenoids has been studied for its antidiarrheal properties [142]. Similarly, the methanolic extract of D. peregrina fruit showed high activity against E. coli (12.6 mm zone of inhibition) and against fungi C. albicans (10.7 mm zone of inhibition) and Penicillium spp. (7.33 mm) [143]. Betulin present in the hexane fraction isolated from the bark of D. paniculata is very efficient against S. dysenteriae, which is responsible for diarrhea (MIC = 30 µg/mL) [144]. However, a study of a reductive green synthesis of nano-sized Ag particles using methanolic root extracts of D. paniculata showed that the maximum activity was displayed against Gram-positive bacteria compared to Gram-negative bacteria. The maximum activity was observed against Penicillium notatum, A. flavus, and Saccharomyces cerevisiae, with moderate activity towards C. albicans and A. niger [145]. In another study of ursane-type triterpenoids obtained from the leaf of D. dendo Welw. Ex Hiern [EtOH−EtOAc (50:50) extract], antimicrobial activity (62% at 10 µg/mL) against Pseudomonas aeruginosa was observed. This Gram-negative bacterium is considered one of the three main causes of human opportunistic infections and has recently been a useful model for the study of biofilm formation, implying antimicrobial resistance to antibiotics [146]. Antiviral Activity Structure–activity relationships between betulinic acid and its synthetic derivatives inhibiting HIV-1 replication, HIV-1 entry, and HIV-protease or reverse transcriptase (RT) have been verified [147,148]. Betulinic acid was identified as a highly promising antiviral (anti-dengue) present in high proportions in most extracts of distinct species of Diospyros, particularly from the bark of D. glans [83]. Aridanin, isolated from methanol extracts obtained from the leaf, stem, and root of D. conocarpa, presents anti-HIV-1IN activity [149]. In a recent study, the antiviral activity of D. anisandra was demonstrated against the influenza virus AH1N1pdm09. The n-hexane fruit extract exhibited HA inhibitory (HAI) activity, and a fraction of it inhibited the hemagglutination from 12.5 up to 100 µg/mL, which was attributed to the synergistic effect of the different compounds present [150]. Previously, possible antiviral activity against influenza A and B viruses has been attributed to a redox effect of isolated zeylanone epoxide [151]. Antiparasitic Activity Using in vitro antimalarial assays, betulinic acid 3-caffeate isolated from the dried leaf, twig, and branch of D. quaesita was shown to be moderately active against both chloroquinesensitive and chloroquine-resistant P. falciparum clones [86]. Lupeol and lupenone, isolated Plants 2023, 12, 2833 23 of 34 from the dichloromethane and ethyl acetate extracts of D. rubra stem, have shown moderate antimalarial activity against P. falciparum [88]. On the other hand, hydroethanolic extracts from the trunk of D. gracilescens and the hexane fraction showed higher activity against promastigote and amastigote forms of L. donovani (IC50 = 5.84 µg/mL and IC50 = 0.79 µg/mL, respectively) [87]. Aridanin isolated from methanol extracts of the leaf, stem, and root of D. conocarpa can be sources of new antitrypanosomal active principles [149]. 2.4.3. Tannins Tannins isolated from Mozambican Diospyros species represent an important class of secondary metabolites with remarkable antimicrobial potential against fungi, bacteria, and yeast [152]. Their mechanism of action involves the disruption of microbial enzymes and cell membranes, although their activities are diverse [153]. In addition, recent research has suggested the ability of tannins to generate hydrogen peroxide, which contributes to their important antibacterial properties [154]. Antibacterial and Antifungal Activities D. melanoxylon bark is another medicinal plant considered to be active against Grampositive and Gram-negative bacteria, which is traditionally used for diarrhea, urinary, and skin troubles and has confirmed claims against E. coli, S. aureus, S. epidermidis, Shigella flexneri, Bacillus licheniformis, Bacillus brevis, Vibrio cholerae, P. aeruginosa, Streptococcus aureus, Candida kruesi, and Bacillus subtilis [155]. Furthermore, it shows promise in the treatment of candidiasis caused by different Candida species (C. viz, C. albicans, C. krusei, C. parapsilosis, and C. tropicalis), with MIC values ranging from 0.375 to 6.0 mg/mL [156]. Extracts derived from the bark of D. melanoxylon are rich in tannins and possess significant potential as antimicrobial agents. In a recent study using strains isolated from humans, it was effective against both Gram-positive and Gram-negative bacteria, suggesting the presence of a broad spectrum of antibiotic compounds or simply general metabolic toxins in the plant methanolic extract [157,158]. In another study conducted in India, acetone ethyl acetate and methanol extracts of D. melanoxylon showed a MIC < 30 µg/mL against Aeromonas hydrophila, Enterobacter aerogenes, E. coli, and Klebsiella pneumoniae [159]. Methanol extract obtained from the bark or seed of D. peregrina, which is rich in tannins and other phenols, was evaluated for its antibacterial potential against the pathogenic bacteria associated with diarrhea. The bark extract demonstrated inhibitory effects against S. aureus, Shigella dysenteriae, E. coli, and P. aeruginosa, while the seed extract inhibited all tested strains except for P. aeruginosa [160]. Similarly, the methanol extract of D. tricolor leaves, known for its abundance of tannins and other phenols, exhibited antibacterial activity against both Gram-positive bacteria (Bacillus cereus and S. aureus) and Gramnegative bacteria (Salmonella typhii and Escherichia coli) [161]. Diospyros kaki Thunb., known as the persimmon tree, is originally from Asia, but it is cultivated in various parts of the world, including Mozambique. Different plant parts are well-known and useful as medicinal plants, and the fruit is known as persimmon. This species has been extensively studied, particularly regarding the antimicrobial activity of the tannins isolated from it. In a study conducted by Liu et al. (2019), the antimicrobial effects of persimmon tannins (PTs) extracted from the fruit of D. kaki against methicillin-resistant Staphylococcus aureus (MRSA) were investigated. The persimmon tannins (MIC = 1000 µg/mL) displayed potential mechanisms of inhibitory activity (i.e., the tannins can change the normal morphology of MRSA and cause severe damage to the cell wall and cell membrane) [152]. In addition, the hydrolysate of condensed tannins (composed of a polymer of flavan-3-ols, such as catechin groups) exhibited high bacteriostatic activity in vitro against the M. avium complex (nontuberculous mycobacteria) that causes opportunistic chronic pulmonary infections [63]. Aqueous extract from the D. kaki fruit was tested in vivo, showing interesting antibacterial activities against Gram-negative strains compared to Gram-positive bacteria, justifying its use in traditional medicine for the treatment and/or management of disorders of the digestive system such as diarrhea [162]. Plants 2023, 12, 2833 24 of 34 The results of another study showed that the condensed tannins extracted from the unripened fruit of D. kaki displayed antibacterial activity against biofilms containing multiple bacteria. It is estimated that intraoral cavity biofilms consist of at least 800 types of bacteria. Therefore, it is suggested that this medicinal plant has a high potential for preventing dental disease and aspiration pneumonitis in geriatric patients and recovering patients when it is added to mouthwash and toothpaste [163]. The in vitro antibacterial potential of D. blancoi was also found against biofilm formation by S. mutans. Both extracts containing tannins and other phenols showed inhibition ranges of 96% for methanol and 95% for ethyl acetate [164]. Recently, Diospyros species rich in tannins have been applied in the development of nanoparticles. For instance, titanium dioxide (TiO2 ) nanoparticles containing D. ebenum leaf extract exhibit excellent antibacterial activity and potential against Gram-negative bacteria E. coli [165]. Silver nanoparticles (AgNPs) containing aqueous extract from the fruit of D. malabarica have demonstrated antibacterial activity against S. aureus at 500 µg/mL and against E. coli at 1000 ug/mL, with an average zone of inhibition size of 8.4 ± 0.3 mm and 12.1 ± 0.5 mm and 6.1 ± 0.7 mm and 13.1 ± 0.5 mm, respectively [166]. Similarly, biogenic silver nanoparticles demonstrated excellent antibacterial activity against a broad range of bacteria, with the highest antibacterial activity observed against E. faecalis (17.77 mm) and B. subtilis (20 mm), also demonstrating good hemocompatibility against humans and rat red blood cells [167]. Antiviral Activity No studies were found on the specific activity of tannins isolated from the native Diospyros species in Mozambique. However, a tannin isolated from D. kaki has been demonstrated to have in vitro antiviral activity against the influenza virus, vesicular stomatitis virus, poliovirus, coxsackievirus, adenovirus, rotavirus, feline calicivirus, mouse norovirus, Sendai virus, and Newcastle disease virus [168]. The results of another study involving D. kaki extracts with tannin contents ranging from 0.08 to ≥0.11 mg/mL demonstrated their capacity to inactivate human noroviruses and bacteriophage MS2, both of which are the cause of gastroenteritis and foodborne illnesses worldwide (i.e., the results suggest that the antiviral effect and astringent effects of tannins are likely related to noroviral genome reduction and MS2 inactivation) [169]. Antiparasitic Activity Species of the genus Diospyros contain a broad spectrum of antimicrobial agents identified using in vitro and/or in vivo methods against strains capable of causing opportunistic infections as well as neglected parasitic diseases. The anthelmintic activity of a D. peregrina fruit extract containing tannins was compared to the standard drug albendazole. The extract was found to be more potent than the selected standard drug at a concentration of 10 mg/mL [170]. According to the WHO, malaria is one of the most widespread neglected diseases in Africa, caused by the parasite Plasmodium and responsible for severe immune complications and deaths. The anti-Plasmodium activity of extracts from various species of the Mozambican Diospyros species has been reported in the literature. Ethyl acetate extract from D. abyssinica leaves showed moderate activity against chloroquine-resistant Plasmodium falciparum (FcB1), while D. mespiliformis, traditionally used to treat malaria, showed potent antimalarial activity in mice infected with Plasmodium berghei and significant inhibition of beta-hematin using an in vitro assay [98]. The antiparasitic activity against Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei was confirmed in several studies on Diospyros species [99]. For example, an acetate leaf extract of D. abyssinica and the isodiospyrin and diospyrin marker compounds isolated from the bark by bioguided fractionation showed high anti-L. donovani activity (IC50 = 1.5 g/mL, extract, and IC50 = 0.5 g/mL, isolated compounds) [65]. Plants 2023, 12, 2833 25 of 34 3. Materials and Methods This review was conducted according to the criteria described in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (http: //www.prisma-statement.org/; accessed on 16 January 2023). For this purpose, the scientific literature data were considered until 10 December 2022. 3.1. Search Strategy The scientific data were collected using the search engines PubMed, Scopus, Web of Science, and Google Scholar, identifying all scientific papers published between 1 January 1970, and 10 December 2022 using the keywords Diospyros AND antibacterial, Diospyros AND antifungal, Diospyros AND antiparasitic, Diospyros AND antiviral, Diospyros AND medicine, Diospyros AND chemical compounds, Diospyros AND biological activity, and Diospyros AND toxicity. 3.2. Study Selection As described in Figure 7, a total of 5528 scientific studies were included in the search and initial data collection based on their title and abstract. After eliminating the duplicates, 2071 studies remained, of which 1852 could not be selected due to a lack of information relevant to this work. After the screening, 279 studies reporting on Diospyros were considered eligible for inclusion in this review. Figure 7. PRISMA flowchart of the screening process in the different databases. ff    Plants 2023, 12, 2833 26 of 34 ff 3.2.1. Criteria for Inclusion and Exclusion of Data Inclusion Criteria  ff ff Related to the Diospyros genus, in particular species of the genus Diospyros present in Mozambican Flora; ff Abstract or full text in English; ff Studies on Diospyros species concerning their medicinal importance.    ff Exclusion Criteria  Duplicate scientific publications; Not directly related to medicinal issues and others related but not with species of  Mozambican Flora;   Containing irrelevant or incomplete information.  4. Conclusions  Species of the genus Diospyros have been studied worldwide, with a significant number exhibiting pharmacological activity. One referenced example, D. kaki, native to East Asia, NaoXinQing, is part of a patented and officially ffi approved traditional Chinese medicine formula for the treatment of stroke. However, there are no studies integrating data on all Diospyros species present in the flora of Mozambique. ffi More than 70% of Mozambique’s population ffi uses medicinal plants for primary health care, and a total of 54.8% of the Diospyros species used in the country’s ethnomedicine are  also used in other regions of Africa; however, the biological potential of most of them is still largely unknown. For example, 64.5% of these species were not tested for their antibacterial ffi properties, namely D. abyssinica subsp. attenuata, D. abyssinica subsp. Chapmaniorum, ffi D. anitae, D. consolatae, D. consolatae-rotundifolia intermediates, D. dichrophylla, D. ferrea, D. inhacaensis, D. kirkii, D. kirkii-mespiliformis intermediates, D. loureiriana subsp. Loureiriana, ffi D. natalensis subsp. Numulária, D. quiloensis, D. senensis, D. truncatifolia, D. usambarensis subsp. Usambarensis/rufescens, D. villosa var. parvifolia, D. villosa var. villosa, D. whyteana, D. zombensis, and Diospyros sp. no. 1 sensu FZ. On the other hand, several isolated compounds of these species (particularly naphthoquinones and triterpenoids) have also been isolated from other species of the genus Diospyros, showing different biological activities including antiviral activity. However, no antiviral studies were found on the Mozambican species. Studies on the antifungal potential of Diospyros are still scarce. In fact, the antifungal activity of 98.14% of the species (D. abyssinica subsp. attenuata, D. abyssinica subsp. chapmaniorum, D. anitae, D. bussei, D. consolatae, D. consolatae-rotundifolia intermediates, D. dichrophylla, D. inhacaensis, D. kabuyeana, D. kirkii, D. kirkii-mespiliformis intermediates, D. loureiriana subsp. loureiriana, D. lycioides Desf. subsp. sericea, D. natalensis subsp. natalensis, D. natalensis subsp. numulária, D. quiloensis, D. rotundifolia, D. senensis, D. squarrosa, D. truncatifolia, D. verrucosa, D. villosa var. parvifolia, D. whyteana, D. zombensis, and Diospyros sp. No. 1 sensu FZ) need to be evaluated, as they are traditionally used to treat skin diseases and diseases of the oral cavity, as well as other diseases where opportunistic fungal infections can co-occur. In addition, antiparasitic activities have been studied in other species of the genus Diospyros, however, 97.21% of Mozambican species (D. abyssinica subsp. attenuata, D. abyssinica subsp. chapmaniorum, D. anitae, D. consolatae, D. consolatae-rotundifolia intermediates, D. dichrophylla, D. ferrea, D. inhacaensis, D. kirkii, D. kirkii-mespiliformis intermediates, D. lycioides Desf. subsp. sericea, D. mafiensis, D. natalensis subsp. numularia, D. quiloensis, D. rotundifolia, D. senensis, D. squarrosa, D. truncatifolia, D. villosa var. villosa, D. villosa var. parvifolia, D. whyteana, D. zombensis, and Diospyros. sp. no. 1 sensu FZ) have not yet had their antiparasitic activities studied. In summary, out of the 31 native and naturalized species in the flora of Mozambique that are used in different regions of Africa, a total of 17 species have not been studied as antimicrobial agents, of which three species, namely D. dichrophylla, D. whyteana, and D. zombensis, have only been studied at the toxicological level. Of the 14 species that have Plants 2023, 12, 2833 27 of 34 already been the subject of antimicrobial studies, D. abyssinica and D. mespiliformis are the best studied. This work provides comprehensive information on the chemical, biological, and toxicological studies of the Diospyros species present in the flora of Mozambique, examining their pharmacological potential in detail. Of the Diospyros plant parts, the root is the bestresearched and documented. The identified studies confirmed ongoing efforts to improve the understanding of the mechanism of action underlying the biological activity, and in particular, the antimicrobial activity of these species, drawing on their traditional use. In addition, several secondary metabolites of Diospyros are currently being investigated for their potential pharmacological applications. However, it is important to emphasize that most of the available data are in vitro assessments of biological activity. Therefore, further efforts are needed to obtain more comprehensive evidence aimed at strengthening the validity and applicability of the results and ultimately contributing to public health benefits, especially in the face of global antimicrobial resistance. Author Contributions: Conceptualization, A.R., R.S., J.F.P. and O.S.; investigation, methodology, and data collection, A.R., R.S., J.F.P. and O.S.; data analysis, A.R., R.S., J.F.P., I.B.M.d.S., E.T.G. and O.S.; writing—original draft preparation, A.R., R.S., J.F.P. and O.S.; writing—review and editing, A.R., R.S., J.F.P., I.B.M.d.S., E.T.G. and O.S.; supervision—O.S.; project administration, O.S.; funding acquisition, O.S. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Foundation for Science and Technology (FCT, Portugal) through the national funds FCT/MCTES to iMed.ULisboa (UIDP/04138/2020). Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Rauf, A.; Uddin, G.; Patel, S.; Khan, A.; Halim, S.A.; Bawazeer, S.; Ahmad, K.; Muhammad, N.; Mubarak, M.S. 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