The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora

Ribeiro, Adriana; Serrano, Rita; da Silva, Isabel B. Moreira; Gomes, Elsa T.; Pinto, João F.; Silva, Olga

doi:10.3390/plants12152833

Open AccessSystematic Review

The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora

by

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

^*

Author to whom correspondence should be addressed.

Plants 2023, 12(15), 2833; https://doi.org/10.3390/plants12152833

Submission received: 26 June 2023 / Revised: 21 July 2023 / Accepted: 29 July 2023 / Published: 31 July 2023

(This article belongs to the Special Issue Medicinal Plants and Their Marker Compounds)

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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

1. Introduction

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 [1,2,3,4]. 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 [5,6,7].

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 [10,11,12].

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 [13,14,15]. For instance, several Diospyros species with antimicrobial potential have been reported [4,16,17,18]. 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.

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].

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].

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 five different countries in Africa (Table 2).

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).

Among all the different Diospyros plant parts used in traditional medicine (Figure 3), 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).

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	Traditional Use	Country	Ref.
D. abyssinica
	leaf	decoction	malaria	Mali	[4,27]
	leaf	decoction	wound healing
	fruit (dry)	decoction	astringent and cholagogue
	fruit (dry)	decoction	gastrointestinal disorders
	bark	unspecified	astringent and antipyretic
	root	decoction	antihelminthic
	root	decoction	abdominal pain, dysentery, and diarrhea
	leaf	juice	snake bite	Mali, Guinea Zimbabwe	[28]
	bark	juice	astringent	Mali, Guinea Zimbabwe	[28]
	bark	decoction	internal injuries	Kenya	[29]
			laxative
			rash
			malaria and ringworm
	leaf	squeeze and apply	ringworm	Uganda	[30]
	seed	squeeze and apply	wound healing		[30]
	leaf	juice	tropical ulcer (skin and soft tissue polymicrobial infection, feet, or lower legs localized)		[31]
	tuber	decoction	upset stomach		[32]
D. anitae
	root	unspecified	dental hygiene	Mozambique	[33]
	root	unspecified	healing of oral wounds	Mozambique	[33]
D. ferrea
	fruit	unspecified	diarrhea and sore throats	India	[34]
			internal bleeding
			renal lithiasis
	root	unspecified	anti-hemorrhagic		[35,36]
			infertility
	bark		oral hygiene
			skin diseases
D. kabuyeana
	root	unspecified	antiviral	Tanzania	[37]
D. loureiroana subsp. loureiroana
	root	chewing stick	oral hygiene	South Africa East Africa	[4]
D. lycioides subsp. sericea
	root bark	decoction	bloody feces	South Africa South Central Zimbabwe	[38,39,40]
			dysentery
			headache
	root	chewing stick	infertility	Namibia Zambia	[41]
D. mafiensis
	root	unspecified	diarrhea	Mozambique Tanzania	[42]
			leprosy
			skin diseases (including fungal infections)
D. mespiliformis
	leaf	decoction	analgesic and antipyretic	Central Southern Eastern Western Africa	[27,43,44,45,46,47]
			antihelminthic
			dermatomycosis
			fungal infections
			induction of childbirth
			hemostatic agent
			malaria, pneumonia, and trypanosomiasis
			sexually transmitted diseases
	leaf and bark	decoction	diarrhea and dysentery
			leprosy
			oral infections
			whooping cough
	leaf	decoction	bruises, bedsores, rash, and wounds
	leaf	decoction	ringworm
	root	chewing stick	oral hygiene
	leaf, bark and root	decoction	toothache	Burkina Faso	[48]
	leaf	decoction	antipyretic	Ghana	[27]
			dermatitis
			diarrhea and dysentery
			malaria
	fruit	decoction	headache
			pneumonia
			rheumatism
	stem bark	decoction	malaria and pneumonia
	root	decoction	infection with fever
	leaf	decoction	antipyretic	Nigeria	[49,50,51]
			antidote for a variety of poisonous substances
			diarrhea and dysentery
			haemostatic agent
			oral infections
			wound healing
	root	decoction	malaria and oral candida infection (used as mouthwash, management of HIV/AIDS opportunistic diseases)	Zambia	[44,52]
	root	infusion	abdominal pain, body and heart pain	South Central Zimbabwe	[53]
	seed	unspecified	antibacterial	Guinea	[4]
D. quiloensis
	stem bark	decoction	malaria	Zambia	[44]
			sexually transmitted diseases
D. rotundifolia
	root	not report	diarrhea	South African	[22]
D. squarrosa
	root	not report	sexually transmitted diseases	Tanzania	[37]
D. usambarensis
	root bark	unspecified	schistosomiasis	Malawi	[54]
	root	chewing stick	oral hygiene	Tanzania	[55,56]
		decoction	fungal infections and overt symptoms of type 2 diabetes (i.e., polyuria, polydipsia, excessive thirst, and sweating)
D. verrucosa
	root	unspecified	leprosy	Tanzania	[4,57]
D. villosa
	leaf	unspecified	gastrointestinal disorders	South African	[24]
	leaf	unspecified	painful fractures	South African	[24]
	root	decoction	gastrointestinal disorders	Mozambique	[4,25,58]
			laxative
			musculoskeletal system
		toothbrush	oral hygiene
		decoction	wounds (skin/subcutaneous tissue)
D. villosa var. parvifolia
	leaf	infusion	emetic	South Africa	[59]
	root	infusion	antihelminthic emetic and flatulence gastrointestinal disorders	South Africa	[59]
D. whyteana
	root	unspecified	antibacterial	South Africa	[60]
			dysmenorrhea
			rash
D. zombensis
	root bark	unspecified	schistosomiasis	Malawi	[4,61]

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	Compounds	Extract	Ref.
D. abyssinica
	root bark	naphthoquinone	plumbagin (2-methyl-5-hydroxy-1,4-naphthoquinone)	P. ether, CF, DCM, H₂O, MeOH, EtOH 80%	[28]
	stem bark	naphthoquinone	diospyrin, isodiospyrin	P. ether, CF, DCM, H₂O, MeOH, EtOH 80%	[64,65]
	leaf	triterpenoid	betulinic acid, betulin and lupeol	MeOH	[64,65]
D. consolatae
	n.r	triterpenoid	betulinic acid, betulin and lupeol	n.r	[4]
	n.r	naphthoquinone	diosindigo A	n.r	[4]
D. dichrophylla
	seed	naphthoquinone	isodiospyrin	Hex	[66]
D. ferrea
	leaf	triterpenoid	pregnenolone and androstan-6-one	MeOH	[67]
	n.r	triterpenoid	β-sitosterol	n.r	[4]
	leaf	monoterpenoid	citronellol	MeOH	[67]
	leaf	diterpenoid	phytol	MeOH	[67]
	leaf	diterpenoid	thunbergol	EtOAc	[67]
	leaf	triterpenoid	betulin, α-amyrin, friedelan-3-one and olen-12-ene	EtOAc	[67]
	fruit	triterpenoid	friedelin, epifriedelinol, lupeol, lupenone, and betulin	n-Hex	[68]
	fruit	triterpenoid	β-sitosterol and stigmasterol	n-Hex	[68]
	root fruit	naphthoquinone	7-methyljuglone, isodiospyrin, diosindigo A and 8-hydroxyisodiospyrin	CF, n-Hex	[68,69]
	root	phenol	gallic acid	EtOH	[70]
	leaf	triterpenoid	friedelin, friedelin-3-ol, taraxerol and taraxerone	EtOH	[4]
	n.r	triterpenoid	ursolic acid	n.r	[4]
D. inhacaensis
	stem	naphthoquinone	7-methyljuglone and diospyrin	n.r	[71]
D. kirkii
	n.r	triterpenoid	bauerenol, betulin and lupeol	n.r	[4]
	n.r		β-sitosterol	n.r	[4]
	n.r	naphthoquinone	diosindigo A	n.r	[4]
D. lycioides
	branche	naphthalene	Diospyroside A, B, C and D	MeOH	[72]
		naphthoquinone	7-methyljuglone and juglone	MeOH	[41]
		triterpenoid	lupeol and ursolic acid	n.r	[53]
	fruit	naphthoquinone	isodiospyrin and bisisodiospyrin	n.r	[71]
	root, stem	naphthoquinone	7-methyljuglone and isodiospyrin	CF	[71]
	n.r	naphthoquinone	mamegakinone, methylnaphthazarin and 8-hydroxyisodiospyrin	n.r	[4]
D. mafiensis
	root bark	naphthoquinone	diosquinone, diosindigo A, 7-methyljuglone, 3-hydroxiquinone, and 6,8-bisdiosquinone	CF, DCM, MeOH	[42,73,74]
	stem bark	naphthoquinone	7-methyljuglone and diosindigo A		[73]
	leaf	triterpenoid	α-amyrin, lupeol and betulinic acid	CF, MeOH	[75]
	bark	naphthoquinone	diosquinone, isodiospyrin, and plumbagin	Ee	[4,52]
	stem bark	triterpenoid	lupeol, betulin, betulinic acid, α-amyrin, and bauerenol	CF	[4,76]
D. mespiliformis
	stem bark, leaf, bark	triterpenoid	betulinic acid, betulin, lupeol, bauerenol, and α-amyrin	CF, MeOH	[4,76]
	leaf	flavonoid	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	n.r	[77]
	root	naphthoquinone	diosquinone, and plumbagin	P. ether	[78]
	root, bark	naphthoquinone	diospyrin	MeOH	[79]
	fruit	naphthoquinone	plumbagin	MeOH	[79]
D. natalensis
	root, stem	naphthoquinone	7-methyljuglone, and diospyrin	n.r	[4]
	n.r	triterpenoid	betulinic acid, α-amyrin, and lupeol	n.r	[4]
	n.r	fatty acid	heptacosanoic acid	n.r	[4]
D. quiloensis
	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]
D. rotundifolia
	n.r	triterpenoid	betulin and lupeol	n.r	[4]
	root	naphthoquinone	7-methyljuglone, neodiospyrin and rotundiquinone	n.r	[71]
	stem	naphthoquinone	7-methyljuglone and diospyrin	n.r	[71]
D. squarrosa
	n.r	naphthoquinone	7-methyljuglone	n.r	[4]
D. usambarensis
	root	naphthoquinone	7-methyljuglone, isodiospyrin, diosindigo A and B, bis-isodiospyrin and mamegakinone	MeOH	[54,80]
	stem bark	naphthoquinone	7-methyljuglone and diosindigo A	MeOH	[54]
D. verrucosa
	root bark	naphthoquinone	diosindigo A, 7-methyljuglone, diosquinone and isodiospyrin	n.r	[57]
	root bark	triterpenoid	betulinic acid and betulin
	stem bark	naphthoquinone	diosindigo A, 7-methyljuglone, diosquinone and isodiospyrin	n.r	[57]
	stem bark	triterpenoid	betulinic acid and betulin	n.r	[57]
D. whyteana
	n.r	naphthoquinone	7-methyljuglone	n.r	[4]
D. zombensis
	bark	triterpenoid	oleanolic acid	MeOH	[4]
	root bark	naphthoquinone	7-methyljuglone, diosquinone, isodiospyrin and mamegakinona	P. ether, MeOH	[4,61]

Extract: Ace—acetone; CF—chloroform; DCM—dichloromethane; Ee—ether; EtOAc—ethyl acetate; EtOH—ethanol; H₂O—water; Hex—hexane; MeOH—methanol; P. ether—petroleum ether; n.r—not reported.

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].

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].

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 have been demonstrated for them, mainly for betulinic acid and its derivatives [83,85,86,87,88].

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].

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 Table 4, Table 5 and Table 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].

In vivo assays have shown that the hexane fraction of D. mespiliformis leaves has anti-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 showed significant antihyperglycemic activity [91]. The root of this species is rich in phenolic acids, especially gallic acid, and is therefore traditionally used as a potent antioxidant [70].

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]; however, 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 chloroquine-sensitive (3D7) and chloroquine-resistant (FcB1) strains of Plasmodium falciparum [31,94].

The decoction of the stem of D. mespiliformis was tested against Plasmodium berghei-infected 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.
Analgesic
D. mespiliformis	SB	CF/lupeol 25 mg/kg, p.o	Pi¹ 2.2 ± 0.2/ asa =1.0 ± 0.3 Pi² 1.98 ± 0.1/ asa =1.15 ± 0.1	Biphasic, Wistar rats	acetylsalicylic acid (asa), 100 mg/kg, p.o.	[76]
D. ferrea	L	CF MeOH	100–300 mg/Kg significant activity	Tail flick method, adult Wistar albino rats	ibuprofen	[100]
D. ferrea	R	CF MeOH	100–200 mg/Kg significant activity	Tail flick method, adult Wistar albino rats	ibuprofen	[101]
Anti-inflammatory
D. abyssinica	Rb	H₂O (1) MeOH (2)	1—IC₅₀ = 16 ± 1 μg/mL 2—IC₅₀ = 86 ± 7 μg/mL	LOX, using soybean lipoxygenase type 1-B	quercetin, IC₅₀ value 11.5 ± 0.6 μg/mL	[27]
D. ferrea	L	CF MeOH	100–300 mg/Kg = 26.2–28.2% 100–300 mg/Kg = 29.6–37.6%	PIPE, adult male Wistar rats	ibuprofen 41.1%	[100]
D. ferrea	R	CF MeOH	100–200 mg/Kg = 37%	PIPE, adult Wistar albino rats	ibuprofen	[101]
D. mespiliformis	Sb	DCM Fraction maximally at 400 mg/kg	Modulation of serum concentrations of Tumour Necrosis Factor alpha and Interleukin 1 beta and 6	Cytokine inhibition, Plasmodium berghei-infected mice	artemether-lumefantrine	[98]
	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, Wistar rats	quercetin, IC₅₀ value 1–46.02 ± 5.46 μg/mL 2–32.05 ± 2.79 μg/mL	[51]
Antihyperglycemic
D. ferrea	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]
Antifungal
D. abyssinica	R	MeOH	Actives in test controlled by conidial suspension	BA, C. albicans C. cucumerinum	methylthiazolyltetrazolium chloride (MTT)	[94]
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-hydroxy- diosquinone	MIC₅₀ = 14.9 µg/mL MIC₅₀ = 39.1 µg/mL	CCA, A. flavus, A. parasiticus	A. parasiticus B62	[42]
	Rb	3-hydroxy- diosquinone	Reduced total aflatoxin, 1.145 to 32 ng/plac	ELISA, A. parasiticus, A. flavus	A. parasiticus B62	[42]
	Rb	diosquinone	MIC₅₀ >100 µg/mL	CCA, A. flavus, A. parasiticus	A. parasiticus B62	[42]
	Rb	diosquinone	Reduced total aflatoxin 1.145 to 45 ng/plac	ELISA, A. flavus, A. parasiticus	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]
D. mespiliformis	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]
	L	H₂O	MIC = 0.08 μg/mL	BD, M. canis	amphotericin B MIC = 0.02 μg/mL	[93]
	B	Ace	IZ: 7 mm (1) IZ: 12 mm (2)	ADD, 1-C. albicans, 2-C. neoformans	nystatin	[96]
D. usambarensis	Rb	7-methyljuglone	MIC = 0.025 μg/mL	BA, C. cucumerinum	miconazole MIC = 0.001 μg/mL	[92]
	Rb	isodiospyrin	MIC = 10 μg/mL	BA, C. cucumerinum	miconazole MIC = 0.001 μg/mL	[54]
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	BD, P. falciparum (FcB1)	chloroquine	[31]
	B	EtOAc	IC₅₀ = 1.5 μg/mL	L. donovani	pentamidine	[65]
	B	EtOAc	IC₅₀ = 5.6 μg/mL	P. falciparum	chloroquine	[65]
	B	diospyrin isodiospyrin	IC₅₀ = 0.5 μM	L. donovani	pentamidine IC₅₀ = 7 μM	[94]
	B	diospyrin isodiospyrin	IC₅₀ = 1.5 μM	P. falciparum (FcB1)	chloroquine IC₅₀ = 0.1 μM	[94]
	R	DCM MeOH	MIC = 500 mg/L	Culex, Anopheles larvae	not identified	[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]
D. verrucosa	Sb	MeOH	IC₅₀ = 1.28 μg/mL	T. brucei (Lister 427)	pentamidine IC₅₀ = 0.000509 μM	[99]
	R	MeOH	IC₅₀ = 2.23 μg/mL	T. brucei (Lister 427)
	L	MeOH	IC₅₀ = 2.99 μg/mL	T. brucei (Lister 427)
D. usambarensis	Rb	7-methyljuglone	Efficiency schistosomiasis MIC = 5 ppm	Biomphalaria glabrata	not identified	[54]
Antioxidant
D. abyssinica	Rb	EtOH (1) MeOH (2) H₂O (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	MeOH	87.36% at 1 mg/mL	DPPH	vitamin E	[106]
	R	MeOH	IC₅₀ = 3.47 ± 0.05 μg/mL	DPPH	ascorbic acid 2.36 ± 0.30 μg/mL trolox 3.43 ± 0.78 μg/mL	[51]
	F	MeOH	IC₅₀ = 6.94 ± 0.49 μg/mL	DPPH		[51]
	B	MeOH	IC₅₀ = 7.82 ± 0.76 μg/mL	DPPH		[51]
	L	EtOAc Fraction	IC₅₀ = 1.08 ± 0.04 μg/ml	DPPH	ascorbic acid 5.08 ± 0.12 μg/mL	[51]
D. villosa	Sb	MeOH	IC₅₀ = 9.53 μg/mL	DPPH	ascorbic acid 10.3 μg/mL	[107]
	L	CF (1) Hex (2)	1-IC₅₀ = 10.7 μg/mL 2-IC₅₀ = 11.8 μg/mL	DPPH	ascorbic acid 10.3 μg/mL	[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; H₂O—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-1-picrylhydrazyl; 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	Toxicity Assay	Results	Ref.
D. abyssinica
	leaf	EtOAc	Cytotoxicity against MRC-5 human diploid embryonic cells, Taxotere^® as standard	IC₅₀ = 6.0 ± 5.0 μg/mL	[31]
	leaf	EtOAc	Cytotoxicity against KB human tumor cell lines (squamous cell carcinoma of the mouth), Taxotere^® as standard	>85% cell inhibition IC₅₀ = 1.0 ± 2.0 μg/mL	[31]
	bark	EtOAc	Cytotoxicity against human KB cell (1) and Rhabditis pseudoelongata (2)	(1) LD₅₀ = 10 μg/mL (2) LD₅₀ = 1 μg/mL	[65]
D. dichhropylla
	seed	DCM:MeOH (1) isodiospyrin (2)	Cytotoxicity using Brine shrimp test (Artemia salina)	1-(LC₅₀ = 29 μg/mL) 2-(LC₅₀ = 0.13 μg/mL)	[66]
D. ferrea
	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]
D. lycioides
	leaf	Ace	Cytotoxicity against BUD-8 cell (human fibroblast cells) in real-time xCELLigence system and 7.4 μg/mL curcumin (control)	IC₅₀ = 500 and 1000 μg/mL	[38]
	leaf	Ace	Cytotoxicity against HeLa cells mobility assayed using the wound healing assay and 7.4 μg/mL curcumin (control)	Nontoxic to the normal cell at 300 μg/mL	[38]
D. loureiriana
	root bark	MeOH	Cytotoxicity against human embryonic kidney cells (HEK293), estimated growth inhibition at 400 μg/ml	IC₅₀ = 100.34 ± 9.85 μg/mL	[105]
	stem bark	MeOH		IC₅₀ = 57.26 ± 0.53 μg/mL	[105]
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 = 25.12 µg/mL 2-LC₅₀ = 69.18 µg/mL 3-LC₅₀ = 120.23 µg/mL 4-LC₅₀ ≤ 8–45.71 µg/mL 5-LC₅₀ = 5.08 µg/mL	[103]
D. mespiliformis
	stem bark root bark	EtOH	In vivo—acute oral toxicity using Wistar rats of both sexes	LD₅₀ = 570 mg/kg Acute toxicity is moderate	[49]
	leaf	MeOH	in vivo—acute oral administration using rats	LD₅₀ ≥ 5 g/kg	[108,109]
	stem bark	MeOH	in vivo—acute oral administration using rats	LD₅₀ ≥ 5 g/kg	[108,109]
	leaf	EtOAc fraction	In vivo—sub-chronic toxicity using rats	LD₅₀ = 750 g/kg	[108]
	stem bark	EtOAc fraction	In vivo—sub-chronic toxicity using rats	LD₅₀ = 500 g/kg	[108]
	root	diosquinone	Cytotoxicity against human glioblastoma cell lines (1) and hormone-dependent human prostate cancer (2)	1-ED₅₀ = 0.18 μg/mL 2-ED₅₀ = 4.50 μg/mL	[84]
D. whyteana
	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]
D. villosa
	root	HydroEtOH 70%	In vivo—acute toxicity using mice	possible renal dysfunction development	[58]
D. zombensis
	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]

Extracts: Ace—acetone; DCM—dichloromethane; EtOAc—ethyl acetate; EtOH—ethanol; H₂O—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%.

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].

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.

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.
D. abyssinica
	bark	BD	EtOAc	12	S. aureus ATCC 6538	DMSO	[65]
D. bussei
	leaf stem bark	BD	MeOH	125	E. coli ATCC 8740	ciprofloxacin 0.63	[99]
	leaf	BD	MeOH	8000	S. aureus ATCC 25923	ciprofloxacin 2.5
	leaf	BD	MeOH	8000	B. cereus ATCC 11775	ciprofloxacin 0.08
	root bark	BD	MeOH	500	E. coli ATCC 8740	ciprofloxacin 0.63
D. kabuyeana
	leaf	BD	MeOH	8000	S. aureus ATCC 25923	ciprofloxacin 2.5	[99]
	leaf	BD	MeOH	4000	B. cereus ATCC 11775	ciprofloxacin 0.08
	stem bark	BD	MeOH	1000	B. cereus ATCC 11775	ciprofloxacin 0.08
	leaf stem bark	BD	MeOH	125	E. coli ATCC 8740	ciprofloxacin 0.63
D. lycioides
	branche	BD	MeOH	1250	S. sanguis, P. gingivalis, S. mutans, P. intermedia	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside A	39	S. sanguis, P. intermedia	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside A	78–1250	P. gingivalis, S. mutans	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside B	39–78	S. sanguis, P. gingivalis	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside B	156–625	P. intermedia, S. mutans	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside C	39–156	P. intermedia, S. mutans	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside C	312–625	P. gingivalis, S, sanguis	alkaloid sanguinarine	[41]
	branche	BD	Diospyroside D	156–312	S. mutans, P. intermedia, P. gingivalis, S. sanguis	alkaloid sanguinarine	[41]
	branche	BD	juglone	19–78	P. intermedia, S. mutans,	alkaloid sanguinarine	[41]
	branche	BD	juglone	39	S. sanguis, P. gingivalis	alkaloid sanguinarine	[41]
	branche	BD	7-methyljuglone	39–156	P. gingivalis, S. mutans	alkaloid sanguinarine	[41]
				78	S. sanguis, P. intermedia	alkaloid sanguinarine	[41]
	leaf	BA	EtOAc	0.10–0.16 *	P. aeruginosa ATCC 27853	p-iodonitrotetrazolium chloride	[38]
			Ace	0.12–0.17 *	P. aeruginosa ATCC 27853	p-iodonitrotetrazolium chloride
	leaf	BA	EtOAc	0.16–0.36 *	S. aureus ATCC 29213	p-iodonitrotetrazolium chloride	[38]
			Ace	0.20–0.45 *
			MeOH	0.16–0.27 *
	leaf	BA	EtOAc	0.05–0.45 *	E. faecalis ATCC 29212	p-iodonitrotetrazolium chloride	[38]
			Ace	0.05–0.45 *
			MeOH	0.05–0.45 *
D. mafiensis
	root bark		DCM	S. aureus B. anthracis IZ: 12 mm	S. typhi, S. boydii, E. coli, K. pneumoniae S. aureus, V. cholerae Proteus sp., B. anthracis	gentamycin ampicillin (20 µg/disc)	[103]
	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	gentamycin ampicillin (20 µg/disc)	[103]
D. mespiliformis
	leaf	ADD	MeOH	167	S. aureus	isoniazid 5.0	[50]
	root	ADD	MeOH	250	S. aureus	isoniazid 5.0	[50]
	leaf	BD	EtOH	12,500–25,000	Salmonella spp., Shigella spp., Campylobacter spp.	ciprofloxacin, cefixime, and gentamicin	[95]
	leaf	BD	Hex (F1) nBOH (F2) EtOAc (F3) H₂O (F4)	(1)78.125–312.5 (2)156.25 (3)78.125–156.25 (4)625–2500	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]
	leaf			625
	root			625 (1) >2500 (2 to 4)
	leaf	AD	H₂O HydroMeOH 10%	250–500 125–500	H. influenzae (6 ci)	ampicillin 0.12–15.6	[112]
			H₂O HydroMeOH 10%	125–250 62.5–125	S. aureus (5 ci)	ampicillin 0.06–0.12
			H₂O HydroMeOH 10%	250–250 125–125	S. pneumoniae (3 ci)	ampicillin 0.015–0.12
			H₂O HydroMeOH 10%	250–250 125–125	S. pyogenes (8 ci)	ampicillin 0.015–0.06
			H₂O HydroMeOH 10%	250–500 125–250	M. catarrhalis (5 ci)	ampicillin 0.12–1.9
	leaf	BD	flavonol O-rhamnoside	9770	S. aureus	not identified	[77]
	root	AD	diosquinone	3–30	S. aureus NCT 6571 S. aureus E3T	ampicillin 5	[78]
	root	AD	diosquinone	15–16	E. coli KL16 P. aeruginosa NCT 6750	gentamicin 2	[78]
	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]
D. natalensis
	leaf	BD	MeOH	250	S. aureus ATCC 25923	ciprofloxacin 0.08	[99]
	leaf		MeOH	1000	B. cereus ATCC 11775	ciprofloxacin 2.5
	leaf		MeOH	500	E. coli ATCC 8740	ciprofloxacin 0.63
	root bark		MeOH	1000	E. coli ATCC 8740	ciprofloxacin 0.63
	stem bark		MeOH	250	E. coli ATCC 8740	ciprofloxacin 0.63
D. rotundifolia
	not reported		Ace	230–1770	S. aureus, E. faecalis, E. coli and P. aeruginosa	not reported	[22]
D. squarrosa
	leaf	BD	MeOH	4000	B. cereus ATCC 11775	ciprofloxacin 2.5	[99]
	leaf	BD	MeOH	250	E. coli ATCC 8740	ciprofloxacin 0.63
	root bark	BD	MeOH	1000	S. aureus ATCC 25923	ciprofloxacin 0.08
	root bark	BD	MeOH	4000	B. cereus ATCC 11775	ciprofloxacin 2.5
	stem bark	BD	MeOH	500	E. coli ATCC 8740	ciprofloxacin 0.63
D. verrucosa
	leaf	BD	MeOH	1000	S. aureus ATCC 25923	ciprofloxacin 0.08	[99]
			MeOH	2000	B. cereus ATCC 11775	ciprofloxacin 2.5
			MeOH	500	E. coli ATCC 8740	ciprofloxacin 0.63
	root bark stem bark	BD	MeOH	<6.25	E. coli ATCC 8740	ciprofloxacin 0.63	[82]
D. villosa
	root	BD	HydroEtOH 70% Ee Fractions	62.5–312.5 15.6–62.5 31.2–62.5	E. faecalis ATCC 435628	not reported	[104]
					E. coli ATCC 25922	not reported
					M. luteus ATCC 10240	not reported
					S. aureus ATCC 25923	not reported
	leaf	DD	AgNPs	IZ: 15 mm	E. coli ATCC 25922	ciprofloxacin 37 mm gentamicin 20 mm	[107]
			AgNPs 80 °C	IZ: 18 mm	S. aureus ATCC 700698	ciprofloxacin 6 mm gentamicin 11 mm
			AgNPs	IZ: 16 mm	S. epidermidis ATCC 12228
			AgNPs	IZ: 16 mm		ciprofloxacin 28 mm gentamicin 20
			Ace	0.05–0.45 *
			MeOH	0.05–0.45 *

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; H₂O—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].

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. [125,126,127]. This compound, isolated from the stem bark of D. bipindensis, also exhibits significant activity against C. albicans [128,129,130].

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].

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 [85,139,140,141]. 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 chloroquine-sensitive and chloroquine-resistant P. falciparum clones [86]. Lupeol and lupenone, isolated 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 Gram-positive 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 Gram-negative 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]. 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].

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.

3.2.1. Criteria for Inclusion and Exclusion of Data

Inclusion Criteria

▪: Related to the Diospyros genus, in particular species of the genus Diospyros present in Mozambican Flora;
▪: Abstract or full text in English;
▪: Studies on Diospyros species concerning their medicinal importance.

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 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.

More than 70% of Mozambique’s population 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 properties, namely 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. loureiriana subsp. Loureiriana, 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 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 best-researched 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.

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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.

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).

Figure 3. Traditional use of Diospyros species: (a) plant part used; (b) type of disease.

Figure 4. Diospyros representatives identified 1,4-naphthoquinones.

Figure 5. Diospyros identified representative lupan-type triterpenoids.

Figure 6. Diospyros dichrophylla (Gand.) De Winter: Detail of fruits in nature, Mandevo, Namaacha district, Maputo, 2010. Photography by Elsa Gomes.

Figure 7. PRISMA flowchart of the screening process in the different databases.

Table 1. Species of the genus Diospyros L. present in Mozambican Flora.

First Discription Year	Scientific Name	Author	Common Name English/Local	MD ¹								IUCN ²
First Discription Year	Scientific Name	Author	Common Name English/Local	N	Z	T	MS	GI	M	CD	Np	IUCN ²
1980	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
1962	D. inhacaensis	F.White	coastal jackal-berry/dodo									LC
1988	D. kabuyeana	F.White	-/-									LC
1873	D. kirkii	Hiern	large-leaved jackal-berry/ cula, fuma, jacualala, mucula, murriba, tendje									LC
1980	D. mafiensis	F.White	-/-									NT
1844	D. mespiliformis	Hochst. ex A.DC.	african ebony, jackal-berry/ muribariba, mucula, muquéué, murriparipa, mutona, mussuma					∇				LC
1956	D. quiloensis	(Hiern) F.White	crocodile-bark jackal-berry/ midodo, murodo									LC
1873	D. rotundifolia	Hiern	dune star-apple/ impapa, mapiti, munhentze				Δ					NE
1861	D. senensis	Klotzsch	spiny jackal-berry/ matamba, mudalima, tombatica									LC
1861	D. squarrosa	Klotzsch	rigid star-berry/cachenz’ere, mpomopo, senzasicana, sicana									LC
1980	D. truncatifolia	Caveney	square-leaved star apple/ impope, mpope									LC
1873	D. verrucosa	Hiern	warty star-apple/djacola, mkonhomo, nkalanongo, riparipa									LC
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 star-apple/chipongoti, nhandima									LC
1805	D. lycioides Desf. subsp. sericea	(Bernh.) De Winter	eastern blue-bush, red star-apple/chitomatomana, m’dima									LC
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
^b D. usambarensis subsp. usambarensis /rufescens		F.White	-/aboba, kidanko, mpome, nhamudima, popa									LC
^c D. villosa (L.) var. villosa		De Winter	hairy star-apple/nhachibabane, nhaurratane, chicanela, chicumbela, chibabane									A
^c D. villosa var. parvifolia		(De Winter) De Winter	hairy star-apple/-									A
^d D. consolatae-rotundifolia intermediates		-	-									A
^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; Δ: 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.

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Ribeiro, A.; Serrano, R.; da Silva, I.B.M.; Gomes, E.T.; Pinto, J.F.; Silva, O. The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora. Plants 2023, 12, 2833. https://doi.org/10.3390/plants12152833

AMA Style

Ribeiro A, Serrano R, da Silva IBM, Gomes ET, Pinto JF, Silva O. The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora. Plants. 2023; 12(15):2833. https://doi.org/10.3390/plants12152833

Chicago/Turabian Style

Ribeiro, Adriana, Rita Serrano, Isabel B. Moreira da Silva, Elsa T. Gomes, João F. Pinto, and Olga Silva. 2023. "The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora" Plants 12, no. 15: 2833. https://doi.org/10.3390/plants12152833

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The Genus Diospyros: A Review of Novel Insights into the Biological Activity and Species of Mozambican Flora

Abstract

1. Introduction

2. Results

2.1. Ethnomedical Use of Diospyros Species of Mozambican Flora

2.2. Chemical Composition of Mozambican Diospyros Species

2.3. In Vitro and In Vivo Biological Activity of Mozambican Diospyros Species and Marker Compounds

2.3.1. Anti-Inflammatory and Analgesic Activity

2.3.2. Antihyperglycemic Activity

2.3.3. Antifungal Activity

2.3.4. Antiparasitic Activity

2.3.5. Antioxidant Activity

2.3.6. Cytotoxicity, Genotoxicity, and Toxicity of Mozambican Diospyros Species

2.3.7. Antibacterial Activity

2.4. Secondary Metabolites of Mozambican Diospyros Species as Potential Antimicrobial Agents

2.4.1. Naphtoquinones

Antibacterial Activity

Antifungal and Antiviral Activities

Antiparasitic Activity

2.4.2. Triterpenoids

Antibacterial and Antifungal Activities

Antiviral Activity

Antiparasitic Activity

2.4.3. Tannins

Antibacterial and Antifungal Activities

Antiviral Activity

Antiparasitic Activity

3. Materials and Methods

3.1. Search Strategy

3.2. Study Selection

3.2.1. Criteria for Inclusion and Exclusion of Data

Inclusion Criteria

Exclusion Criteria

4. Conclusions

Author Contributions

Funding

Data Availability Statement

Conflicts of Interest

References

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