Biological Activity of Stilbenoids Against Fungal, Parasitic, and Viral Pathogens

Abstract

Stilbenoids are plant-derived chemical compounds that are classified as phytoalexins; recent focus has been drawn, especially on astringin, piceid, piceatannol, pterostilbene, pinosylvin, and resveratrol. These substances have been extensively studied for a variety of beneficial properties, including their effects on pathogenic microorganisms, parasites, and viruses. In their antifungal capacity, they are effective against Aspergillus spp., Botrytis spp., Candida spp., Trichophyton spp., and other fungi; tested stilbenoids have exhibited fungicidal and fungistatic effects, and inhibition of biofilm formation. Against parasites, they are effective against Echinococcus spp., Leishmania spp., Schistosoma spp., Trypanosoma spp., Toxoplasma spp., among others. Relevant action mechanisms include a reduction in parasitic enzymatic activity and inhibition of proliferation. They are also effective against different DNA and RNA viruses; the relevant mechanisms comprise reduction in viral replication, inhibition of viral genome expression, and viral attachment to cells. The toxicity of stilbenoids has been reviewed in recent papers, and, in most cases, the effective concentrations applied are well below the toxicity limit.

1. Introduction

In the latter half of the 20th century and afterwards, the development and mass production of a number of different pharmacological agents and drugs have provided treatment and curative solutions for a variety of different pathologies of different etiologies [1,2]. However, even when such solutions are effective, they may be associated with side effects or adverse effects of varying severity, which limit their use [3,4,5,6,7,8,9]. Resistance to pharmacotherapy raises further issues in the treatment of infectious diseases [10,11,12]. It is mostly this resistance to drugs that has fueled the search for alternative therapeutic agents; plant-derived compounds are identified based on the meticulous analysis of the chemical constituents of their extracts alongside ethnomedical and ethnobotanical reports [13,14,15,16,17,18,19,20,21]. Numerous compounds have been identified in phytochemical studies, such as kaempferol, capsaicin, pinosylvin, quercetin, and piperine, among others [22,23,24,25,26,27,28,29,30,31,32].

One of the most studied categories of natural compounds is stilbene phytoalexins. Stilbenes are plant-synthesized polyphenolic substances whose purpose is to defend the plants from bacterial and fungal infections [33], hence their classification as phytoalexins [34]. They play a very important role in the plant kingdom, being a crucial line of defense against infections and harsh climate conditions [35,36,37,38].

Stilbenoids have a common core represented by an ethylene moiety in the middle of two benzene rings; the principal structural factor determining their functionality is the location and number of hydroxyl groups [39,40]. They are derived from the phenylpropanoid pathway; their biosynthesis is catalyzed by stilbene synthase, which has evolved from chalcone synthase, whose activity in plants is tissue-specific and development stage-specific [36,41,42].

The most important stilbenoid phytoalexins are astringin, resveratrol, pinosylvin, piceid, piceatannol, and pterostilbene, even though hundreds of stilbenoids occur naturally via different chemical reactions [43]. This review focuses on the most well-known and researched stilbenoids (Table 1).

Table 1. Basic data on the stilbenoids discussed in the text, organized alphabetically.

Stilbenoid	Chemical Name	Chemical Class	Water Solubility	First Isolation/Identification	References
Astringin	3-β-D-glucoside of piceatannol	Glycosides	730 μg/mL	1962	[44,45]
Piceid	resveratrol 3-β-mono-D-glucoside		1260 μg/mL	1940	[46,47]
Piceatannol	3′,4′,3,5-tetrahydroxy-trans-stilbene	Aglycones	161 μg/mL	1948/1963	[48,49,50]
Pinosylvin	3,5-dihydroxy-trans-stilbene		Practically insoluble 1	1939	[51,52,53]
Pterostilbene	trans-3,5-dimethoxy-4′-hydroxystilbene		12.7 μg/mL	1940	[54,55,56]
Resveratrol	3,5,4′-trihydroxy-trans-stilbene		52.2 μg/mL	1940	[48,57]

¹ Small values comparable to other stilbenoids when complexed with bile salts.

Table 1. Basic data on the stilbenoids discussed in the text, organized alphabetically.

Stilbenoid	Chemical Name	Chemical Class	Water Solubility	First Isolation/Identification	References
Astringin	3-β-D-glucoside of piceatannol	Glycosides	730 μg/mL	1962	[44,45]
Piceid	resveratrol 3-β-mono-D-glucoside		1260 μg/mL	1940	[46,47]
Piceatannol	3′,4′,3,5-tetrahydroxy-trans-stilbene	Aglycones	161 μg/mL	1948/1963	[48,49,50]
Pinosylvin	3,5-dihydroxy-trans-stilbene		Practically insoluble 1	1939	[51,52,53]
Pterostilbene	trans-3,5-dimethoxy-4′-hydroxystilbene		12.7 μg/mL	1940	[54,55,56]
Resveratrol	3,5,4′-trihydroxy-trans-stilbene		52.2 μg/mL	1940	[48,57]

¹ Small values comparable to other stilbenoids when complexed with bile salts.

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is the most well-known and studied stilbene [58,59]; usually, in the human food chain, it is contained in grapes and wine products, where the trans form prevails [60,61]. A number of researchers have concentrated on determining the content of resveratrol and other polyphenols in different types of wine [62]. Resveratrol has been under intense research for its different beneficial properties in human health [63,64].

Astringin can be derived from pinosylvin, resveratrol, or piceatannol via different metabolic pathways. Astringin is relatively unstable in the air, and this precludes its facile use in standard antimicrobial tests [65]. As of yet, there is not a significant corpus of scientific literature on the properties and potential uses of astringin [45].

Piceid, also known as polydatin [47], is a major derivative of resveratrol in grape juices [66]; pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) is a structural analog of resveratrol, with demonstrated anti-inflammatory, antioxidant and anticancer capacity [54,67,68], which has been isolated from a number of plants, many of which have been used in traditional medical systems [69,70]. The very close similarity of pterostilbene to resveratrol means that it can potentially have similar health benefits, and be even more potent in some regards [71,72]; for instance, its beneficial properties in glucose and lipid metabolisms have been demonstrated in a series of experiments, and their applications would have system-wide impact [73,74,75,76].

Pinosylvin (3,5-dihydroxy-trans-stilbene) is a stilbenoid polyphenol that is principally found in plants of the Pinaceae family. Numerous studies have demonstrated its various health-related benefits, such as its antioxidant, anti-inflammatory, and anticancer potential, while Pinaceae plants themselves have been used in many traditional medical systems [51].

Piceatannol (3,3′,4,5′-tetrahydroxy-trans-stilbene) has poor water solubility as it is relatively nonpolar, with the trans isomer being abundant [49]. It was originally isolated from Vouacapoua americana [77]. Recent research has revealed its anticarcinogenic, antioxidant, antidiabetic, and anti-inflammatory potential [78], among others.

The chemical structures of the above-mentioned substances are represented in Figure 1.

Figure 1. Chemical structures of the most relevant stilbenoids. Marvin JS was used for drawing, displaying, and characterizing chemical structures, Marvin JS 25.3.0, Chemaxon (http://chemaxon.com/ (accessed on 6 February 2026)), based on public chemical data [79].

All the aforementioned stilbenoids can be found in numerous different plant species (Table 2).

Table 2. Availability in nature of the most frequent stilbenoids; the plants are organized alphabetically by family, genus, and species—regarding resveratrol, only the most important plant species are mentioned.

Compound	Family	Genus	Species	References
Astringin	Myrtales	Myrtaceae	Ε. astringens	[80]
	Pinaceae	Picea	P. abies L.	[81]
			P. jezoensis	[82]
			P. sitchensis	[83]
Piceatannol	Euphorbiaceae	Euphorbia	E. lagascae	[84]
	Fabaceae	Arachis	A. hypogaea	[85]
		Cassia	C. abbreviata	[86]
		Vouacapoua	V. americana	[77]
	Musaceae	Ensete	E. glaucum	[87]
		Musa	M. acuminata
			M. itinerans
	Myrtaceae	Rhodomyrtus	R. tomentosa	[88]
	Passifloraceae	Passiflora	P. caerulea	[77,89]
			P. edulis
			P. longifilamentosa
	Pinaceae	Picea	P. jezoensis	[82]
	Polygonaceae	Rheum	R. rhaponticum L.	[90]
	Vitaceae	Vitis	V. rotundifolia Michx.	[91]
			V. vinifera	[92,93]
Piceid	Pinaceae	Picea	P. jezoensis	[82]
	Polygonaceae	Polygonum	P. cuspidatum	[94]
	Vitaceae	Vitis	V. vinifera	[95,96]
Pinosylvin	Fabaceae	Arachis	A. hypogaea	[97]
		Cajanus	C. cajan	[98]
	Rhamnaceae	Hovenia	H. dulcis Thunb.	[99]
	Lauraceae	Lindera	L. reflexa Hemsl	[100]
	Myrtaceae	Agonis	A. flexuosa	[101]
	Pinaceae	Picea	P. abies	[102]
			P. glauca	[103]
		Pinus	P. banksiana	[104,105]
			P. brutia Hen.	[106]
			P. caribaea	[107]
			P. cembra	[108]
			P. contorta	[108]
			P. densiflora	[109]
			P. halepensis Mill.	[110]
			P. merkusii	[111]
			P. nigra Arn.	[112]
			P. palustris	[113]
			P. pinaster	[114]
			P. resinosa	[105]
			P. roxburghii Sargent	[115]
			P. strobus	[113]
			P. sibirica	[108]
			P. sylvestris	[116]
			P. taeda	[117]
	Stemonaceae	Stemona	S. cf. peirrei	[118]
			S. collinsae	[119]
			S. tuberosa	[120]
Pterostilbene	Ericaceae	Vaccinium	V. ashei	[121]
			V. virgatum	[122]
	Fabaceae	Pterocarpus	P. marsupium	[122]
			P. santalinus	[122]
	Vitaceae	Vitis	V. amurensis	[123]
			V. vinifera	[122,124]
Resveratrol	Moraceae	Artocarpus J. R. et G. Forst.	A. lacucha (Roxb.) Buch.	[93]
		Cudrania Trec.	C. cochinchinensis Lour.	[93]
		Morus L.	M. alba L.	[93]
			M. macroura Miq.
			M. nigra L.
	Polygonaceae	Polygonum	P. cuspidatum	[94,125]
			P. grandiflorum	[57]
		Rheum	R. rhaponticum L.	[90]
	Myrtaceae	Eucalyptus L. Herit	E. tereticornis Smith	[93]
	Ranunculaceae	Paeonia L.	P. suffruticosa Andr.	[93]
			P. suffruticosa Andr. var. papaveracea (Andr.) Kerner
	Vitaceae	Ampelopsis Michaux	A. cantoniensis (Hook. & Arn.) K. Koch	[93]
			A. japonica (Thunb.) Makino
		Cissus L.	C. quadrangularis L.	[93]
			C. sicyoides L.
		Parthenocissus Planch.	P. tricuspidata (S. et Z.)	[93]
			P. quinquefolia (L.) Planch.
		Tetrastigma Planch.	T. hypoglaucum Planch ex Franch.	[93]
			T. serrulatum (Roxb.) Planch
		Vitis	V. amurensis	[63]
			V. vinifera	[93]

Various methods have been proposed for the production of different stilbenoids, as they are promising targets for cosmetic applications and as food supplements [126]. For example, the market for resveratrol is expanding, in parallel with the scientific interest [126].

In this review, we aim to provide a comprehensive overview of the antifungal, antiviral, and antiparasitic activity of the aforementioned stilbenoids, along with the known associated mechanisms; antibacterial applications have been discussed by a number of authors (e.g., [127,128,129,130,131,132,133,134,135]). An overview of the medical relevance and summary of the presented actions are also provided, alongside potential issues of toxicity and bioavailability.

2. Antifungal Activity of Stilbenoids

Fungal infections still represent an appreciable threat to human health and well-being, even if the number of pathogenic fungi is lower compared to that of pathogenic bacteria [136], and most fungal infections are not life-threatening in the absence of risk factors [137,138,139]. At the same time, resistance to antifungal agents represents another therapeutic challenge [140,141,142]. Currently, there is a large corpus of data on the antifungal potential of the discussed stilbenoids, albeit mostly in vitro (Table 3).

Table 3. Available data on the antifungal potential of the stilbenoids discussed in the text, organized alphabetically by genus and species, and then chronologically (potency reported as per the original research).

Genus	Species	Study Type	Compound	Stilbenoid Origin	Concentration	Effect (Mechanism)	Reference
Aspergillus	A. flavus	In vitro	Pterostilbene	Pure compound	15.94 μg/mL (EC50)	Inhibition of mycelial growth and of aflatoxin production	[143]
	A. fumigatus	In vitro	Pinosylvin	Pinus spp.	106.12 μg/mL and 10,612 μg/mL (concentrations used)	Inhibition of germination and growth	[144]
Candida	C. albicans	In vitro	Pinosylvin	Pure compound	62.5 μg/mL (MIC)	Inhibition of growth	[145]
		In vitro	Resveratrol	Pure compound	20 μg/mL (MIC)	Fungicidal effect	[146]
		In vitro	Pinosylvin	Pinus spp.	106.12 μg/mL and 10.612 μg/mL (concentrations used)	Inhibition of growth	[144]
		In vitro	Astringin	Pure compound	>81.20 μg/mL (MIC80)	No appreciable growth inhibition at tested concentrations	[147]
			Pinosylvin	Pure compound	$\ge$42.45 μg/mL (MIC80)	No appreciable growth inhibition at tested concentrations
			Pterostilbene	Pure compound	25.60 μg/mL (MIC80)	Inhibition of growth
			Resveratrol	Pure compound	>45.65 μg/mL (MIC80)	No appreciable growth inhibition at tested concentrations
		In vitro	Pterostilbene	Pure compound	32 μg/mL (MIC80)	Inhibition of biofilm formation	[148]
		In vivo			32 & 64 μg/mL (concentrations preventing biofilm formation in vivo)
		In vitro	Resveratrol (only analogues investigated)	Pure compound	n/a (only analogues investigated)	Fungicidal effect	[149]
		In vitro	Pterostilbene	Pure compound	16 & 128 μg/mL (action against biofilm formation & mature biofilm, respectively)	Inhibition of biofilm formation and action against mature biofilm	[121]
		In vitro	Pterostilbene	Pure compound	5 & 10 μg/L (MIC50 & MIC80 respectively)	Inhibition of biofilm formation and disruption of existing biofilm	[150]
			Resveratrol	Pure compound	160 & 175 μg/L (MIC50 & MIC80 respectively)
		In vitro	Resveratrol	Pure compound	1200 & 3200 μg/mL (cis and trans form, respectively)	Promotion of susceptibility to azole antifungal agents	[151]
Cladosporium	C. herbarum	In vitro	Pinosylvin	S. collinsae	n/a (only structurally similar stilbenoids were tested)	Inhibition of growth	[119]
		In vitro	Pinosylvin	S. cf. pierrei	10 μg/mL (EC50)	Inhibition of growth	[118]
Epidermophyton	E. floccosum	In vitro	Resveratrol	Pure compound	25–50 μg/mL (IC75)	Fungicidal effect (precise mechanism unknown; probably some type of inhibition of membrane protein functionality)	[152]
Microsporum	M. gypseum	In vitro	Resveratrol	Pure compound	25–50 μg/mL (IC75)	Fungicidal effect (precise mechanism unknown; probably some type of inhibition of membrane protein functionality)	[152]
Trichophyton	T. mentagro-phytes	In vitro	Resveratrol	Pure compound	25–50 μg/mL (IC75)	Fungicidal effect (precise mechanism unknown; probably some type of inhibition of membrane protein functionality)	[152]
	T. tonsurans	In vitro	Resveratrol	Pure compound	25–50 μg/mL (IC75)	Fungicidal effect (precise mechanism unknown; probably some type of inhibition of membrane protein functionality)	[152]
	T. rubrum	In vitro	Resveratrol	Pure compound	25–50 μg/mL (IC75)	Fungicidal effect (precise mechanism unknown; probably some type of inhibition of membrane protein functionality)	[152]
		In vitro	Astringin	Pure compound	>81.20 μg/mL (MIC80)	No appreciable growth inhibition at tested concentrations	[147]
			Pinosylvin	Pure compound	21.22 μg/mL (MIC80)	Inhibition of growth
			Pterostilbene	Pure compound	6.40 μg/mL (MIC80)	Inhibition of growth
			Resveratrol	Pure compound	>45.65 μg/mL (MIC80)	No appreciable growth inhibition at tested concentrations
Trichosporon	T. beigelii	In vitro	Resveratrol	Pure compound	10 μg/mL (MIC)	Fungicidal effect	[146]
	T. cutaneum	In vitro	Resveratrol	Pure compound	80 μg/mL (MIC80)	Inhibition of biofilm formation and disruption of existing biofilm	[153]

2.1. Antifungal Activity Against Aspergillus spp.

2.1.1. Aspergillus flavus

This fungus, alongside others of its species, is associated with the production of harmful metabolites called aflatoxins [154,155]. They can contaminate food sources such as nuts and grapes [154,155]. As such, this microorganism represents a notable threat to public health safety and causes significant economic losses due to the measures that have to be taken in order to prevent aflatoxicosis [156]. Pterostilbene was found to have good antifungal activity against A. flavus. Apart from an EC₅₀ lower than that of natamycin, it could also inhibit the infection of peanuts, at concentrations of 250 and 500 μg/mL [143].

2.1.2. Aspergillus fumigatus

This is a ubiquitous saprophytic fungus, which can cause aspergillosis, one of the most clinically relevant opportunistic fungal infections [157,158]. While immunocompetent hosts are typically resistant to infection, a variety of diseases from bronchopulmonary aspergillosis to invasive aspergillosis can affect immunocompromised patients [159,160]. Due to its high clinical impact and increasing resistance to antifungals, A. fumigatus is a major target for the development of novel agents [161].

The antifungal effects of knotwood extracts of different Pinus species in general must be attributable, at least in part, to their content of pinosylvin and its derivatives. These are more active when in their pure form, but the action mechanism remains unknown [144].

2.2. Antifungal Activity Against Candida albicans

This fungus is a common commensal yeast and is one of the leading causes of opportunistic fungal infections [162]. It may colonize the oral cavity, genitourinary mucosa, and gastrointestinal tract without causing disease; transitioning to a pathogenic state can occur in host immunity disruptions or microbial imbalances [163]. It may be responsible for a wide spectrum of infections, from superficial mucocutaneous candidiasis to life-threatening infections and disseminated disease [164].

Pinosylvin, both as a pure compound and as a component in extracts, proved effective against C. albicans, although the precise mechanism was not elucidated [144]. A number of other researchers have also demonstrated its effectiveness against this pathogen [145,165].

Pterostilbene was tried both in vivo and in vitro by Li et al. [148], and was found to be able to inhibit biofilm formation in both settings. Biofilm inhibition, both for pterostilbene and some analogues, was confirmed by the research of Hu et al. [121]; at lower concentrations, pterostilbene could inhibit biofilm formation, and at higher concentrations, it was also effective against mature biofilm. An experimental study, conducted in vitro by Kingsbury et al. [147], where astringin, pinosylvin, pterostilbene, and resveratrol were tested, revealed that only pterostilbene inhibited C. albicans growth in low concentrations. They also noted the potential of combining fungicidal phytochemicals with antifungal drugs.

The fungicidal potential of resveratrol, and some of its structural analogues, against C. albicans has long been recognized [145,149]. It also exhibits a good biofilm formation inhibitory potential and could disrupt already formed biofilm in the study of Kolouchová et al. [150]; the same results were obtained for pterostilbene in this study. Surprisingly, Weber et al. [166] reported no effectiveness of resveratrol against C. albicans and other Candida species. Another study by Wang et al. [151] found that resveratrol, in either its cis or trans confirmation, did not have an appreciable antifungal effect until very high concentrations in excess of 1000 μg/mL, at which point its solubility decreased. It did, however, exhibit a synergistic effect with azole antifungals.

2.3. Antifungal Activity Against Cladosporium herbarum

This microorganism contributes to the environmental fungal bioaerosols, and it is a well-recognized source of inhalant allergens associated with allergic rhinitis, asthma exacerbations, and hypersensitive reactions [167,168,169]. Human infections are rare, but may occur in immunocompromised individuals; otherwise, there is little available evidence of its pathogenicity. Pinosylvin was found to have a notable effectiveness, with an EC₅₀ of just 10 mg/mL [118]; similar results were recorded by Pacher et al. [119].

2.4. Antifungal Activity Against Epidermophyton floccosum

This pathogen is among the ones most often associated with dermatophytia [170,171,172], although recently, a reduced prevalence has been noted [171,172]. The associated conditions are tinea at the level of the trunk (corporis), the groin (cruris), the feet (pedis), and the nails (ungium) [171,172], with the first three being the most common [171]. Against E. floccosum, resveratrol was found to be effective at relatively low concentrations, compared to its toxicity limit. The precise mechanism, although unknown, may have something to do with inhibition of the functionality of membrane proteins [152].

2.5. Antifungal Activity Against Trichophyton spp.

2.5.1. Trichophyton mentagrophytes

This fungus has a global distribution, affecting humans and animals alike [173], causing diverse dermatophytosis [174]. There has recently been a high rise in the prevalence of genotype VII [173]; the microorganism thus constitutes an emerging zoonosis [173] which can pose a problem for public health, particularly in males of low socioeconomic background [175]. Resistance to commonly used antifungals, such as fluconazole and terbinafine, has been recorded [176,177,178].

Against T. mentagrophytes, as well as against other Trichophyton spp., resveratrol had a fungicidal effect, although the precise mechanism remains unknown [152]. The relatively low concentrations needed are far below the toxicity limit and allow for effective local application.

2.5.2. Trichophyton rubrum

This microorganism is the one most commonly implicated in superficial infections of fungal etiology all over the world [177,178], being more active during the summer and usually affecting people over 50 years old, especially males [178]. The main associated pathology is tinea pedis, and to a lesser extent, tinea ungium and tinea cruris [178]. Although it is currently considered sensitive to the action of terbinafine [177], a drug-resistant strain was recently isolated in China [179].

Against T. rubrum, as well as against other Trichophyton spp., resveratrol had a fungicidal effect, although the precise mechanism remains unknown [152]. Given that the necessary concentration for a meaningful inhibition is relatively low, and far below the known toxicity limits, it is believed that local application will be effective. Amongst all the stilbene phytoalexins, only pinosylvin and pterostilbene were found to inhibit T. rubrum growth in reasonably low concentrations [147].

2.5.3. Trichophyton tonsurans

This fungus is among the main causes of tinea capitis [180] and tinea corporis [180,181], although there also exist asymptomatic carriers [181]. An association with contact sports has been established [181]. Resistance to antifungal agents, such as fluconazole and terbinafine, has been noted [182,183].

Against T. tonsurans, as well as against other Trichophyton spp., resveratrol had a fungicidal effect, although the precise mechanism remains unknown. Bearing in mind that the concentration needed is relatively low, there is the possibility of local application without exceeding the toxicity limit [152].

2.6. Antifungal Activity Against Trichosporon spp.

2.6.1. Trichosporon beigelii

The potential of this fungus to cause severe infections, resistant to treatment, in immunocompromised patients has been demonstrated since the 1990s [184]. While very rare, infections with this opportunistic pathogen may even cause severe infective endocarditis, where the difficulty in treatment is complicated by difficulties in early diagnosis [185]. Against this pathogen, resveratrol was found to be as potent as amphotericin B [146].

2.6.2. Trichosporon cutaneum

This fungus is associated with white piedra and onychomycosis [186,187]. Its biofilm production plays a major role in its virulence [187], and it has been shown to act as an opportunistic pathogen in patients with suppressed immune responses [186]. Some level of resistance to fluconazole has been identified [187]. Against T. cutaneum, as well as against other Trichosporon spp., resveratrol caused inhibition of biofilm formation and disruption of existing biofilm [153].

3. Antiparasitic Activity of Stilbenoids

Parasites represent a widespread cause of morbidity and mortality, especially in areas where they are endemic [188,189,190]; their spread may be facilitated by a number of factors [191,192]. They therefore represent a considerable potential burden of disease [193,194,195], and some parasites have developed resistance to antiparasitic drugs [196,197]. The need to develop novel therapeutic approaches is thus apparent; stilbenoids may represent potent antiparasitic agents, based on recent research results (Table 4).

Table 4. Available data on the antiparasitic potential of the stilbenoids discussed in the text, organized alphabetically by genus and species, and then chronologically (potency reported as per the original research).

Genus	Species	Study Type	Compound	Extract from	Concentration	Mechanism	Year	Reference
Echinococcus	E. granulosus	In vitro	Resveratrol	Pure compound	2.28, 11.41, and 22.82 μg/mL (concentrations used)	Reduction in viability, ultrastructural damage, and increased autophagy gene transcription	2023	[198]
		In vivo			100 mg/kg per day (for 14 d)	n/a (ineffective)
	E. multilocularis	In vitro	Resveratrol	Pure compound	2.28, 11.41, and 22.82 μg/mL (concentrations used)	Reduction in viability, ultrastructural damage, and increased autophagy gene transcription	2023	[198]
		In vivo			100 mg/kg per day 1 (for 14 d)	n/a (ineffective)
Hymenolepis	H. diminuta	In vivo	Resveratrol (alone and in extract form)	Carex baccans Nees roots	Various doses for the whole extract and for resveratrol separately	Reduction in worm burden	2015	[199]
Naegleria	N. fowleri	In silico	Piceid	Gossypium hirsutum	n/a (molecular docking study)	S-adenosyl-L-homocysteine hydrolase inhibition	2025	[200]
Leishmania	L. amazonensis	In vitro	Resveratrol (with amphotericin B)	Pure compound	9.59 μg/mL (IC50 − amastigotes) and 6.16 μg/mL (IC50 − promastigotes)	Inhibition of proliferation and incidental parasite death	2014	[201]
		In vivo	Piceatannol	Pure compound	11 μg/mL (amastigotes) and 15.88 μg/mL (IC50 − promastigotes)	Alteration of mitochondrial membrane potential	2015	[202]
			Pterostilbene		8.51 μg/mL (IC50 − amastigotes) and 4.54 μg/mL (IC50 − promastigotes)	Reduction in pro-inflammatory mediators in infected macrophages and NO levels
		In vitro	Resveratrol analogues	Pure compound	Various (depending on parasite type and stage)	Inhibition of mitochondrial function, membrane permeabilization, cell cycle inhibition, accumulation of autophagic vacuoles	2019	[203]
	L. braziliensis	In vitro, in silico	Resveratrol & analogues	Pure compound	28.41 μg/mL (IC50 − amastigotes) and 17.15 μg/mL (IC50 − promastigotes)	Inhibition of trypanothione reductase	2019	[204]
		In vitro	Resveratrol analogues	Pure compound	Various (depending on parasite type and stage)	Inhibition of mitochondrial function, membrane permeabilization, cell cycle inhibition, accumulation of autophagic vacuoles	2019	[203]
	L. donovani	In vitro	Piceatannol	Euphorbia lagascae seeds	4.2 and 7.4 μg/mL (LD50)	Toxic action—probably protein kinase inhibition	2008	[84]
	L. infantum	In vitro	Piceatannol	Euphorbia lagascae seeds	3.9 μg/mL (LD50)	Toxic action—probably protein kinase inhibition	2008	[84]
		In vitro	Resveratrol	Pure compound	Various (depending on parasite type and stage)	Inhibition of mitochondrial function, membrane permeabilization, cell cycle inhibition, accumulation of autophagic vacuoles	2019	[203]
	L. major	In vitro	Resveratrol	Pure compound	45 μg/mL	n/a	2007	[205]
		In vitro	Piceatannol	Euphorbia lagascae seeds	5.7 μg/mL (LD50)	Toxic action—probably protein kinase inhibition	2008	[84]
		In vitro	Resveratrol analogues	Pure compound	<35 μg/mL (concentration of moderate antipromastigote activity)	Inhibition of NO production and cytotoxicity towards host cells	2013	[206]
		In vitro	Resveratrol	Pure compound	16.23 μg/mL (IC50)	n/a	2022	[207]
		In vivo			10 mg/Kg	n/a
Plasmodium	P. falciparum	In vitro	Piceid	Parthenocissus tricuspidate leaves	5.15 ± 0.47 μg/mL (IC50)	n/a	2007	[208]
			Resveratrol		13.24 ± 1.73 μg/mL (IC50)
Schistosoma	S. mansoni	In vitro	Resveratrol $\pm$ praziquantel/artesunate	Pure compound	2.28, 11.41, and 22.82 μg/mL	Synergistic action with antiparasitic drugs	2019	[209]
Toxoplasma	T. gondii	In vivo	Resveratrol (±sulfamethoxazole-trimethoprim)	Pure compound	Different doses depending on test groups	Reduction in oxidative species and increase in antioxidant species (protective effective for host organism)	2016	[210]
		In vitro	Piceatannol	Pure compound	15 mg/kg	Inhibition of proliferation	2022	[211]
		In vivo			6.86 μg/mL (EC50)	Unclear—possibly similar to that of resveratrol
		In vitro	Piceatannol	Pure compound	24.42 μg/mL (cells treated for 12 h)	Induction of mitochondrial dysfunction and reduction in ATP levels	2025	[212]
		In vivo			50 mg/kg 2	n/a
		In vitro	Resveratrol	Pure compound	12.46 μg/mL (IC50)	Reduction in growth, apoptosis; promotion of apoptosis of infected cells	2019	[213]
Trichinella	T. spirallis	In vitro	Resveratrol	Pure compound	Different concentrations depending on time of exposure and parasite stage	n/a	2009	[214]
Trypanosoma		In vivo	Resveratrol	Pure compound	15 mg/kg (starting at 60 days post-infection, for 30 days)	Cardioprotective effect via reduction in parasitaemia, activation of the AMPK pathway, and reduction in oxidative stress	2016	[215]
	T. cruzi	In vitro	Resveratrol	Pure compound	17.57 μg/mL (IC50 − inhibition of trypomastigote activity); 22.37 μg/mL (IC50 − inhibition of epimastigote growth)	Inhibition of trypanosomal activity due to inhibition of arginine kinase	2016	[216]
		In vitro	Resveratrol	Pure compound	57.06 μg/mL (IC50 − inhibition of replication); 11.48 μg/mL (IC50—trypanosidal activity)	Diminishing epimastigote growth; interfering with life cycle	2017	[217]

¹ Intracellular and extracellular stage, respectively. ² Only concentration used; mice survived for more days but eventually died.

3.1. Antiparasitic Activity Against Echinococcus spp.

Echinococcus spp., and its most clinically relevant species, E. granulosus, are responsible for echinococcosis, characterized by hydatid cysts in the internal organs of humans or other animals, who serve as the intermediate hosts [218]. The disease presents a worldwide distribution [218] and generally has a favorable prognosis if detected early [219], but may carry increased morbidity and mortality in certain patient subsets [220,221,222]. Current therapeutic agents may potentially be associated with serious adverse effects [223].

The effects of resveratrol against Echinococcus species were recently studied by the team of Loos et al. [198] both in vivo and in vitro. In vitro results revealed that resveratrol is effective against E. granulosus and E. multilocularis, as it causes ultrastructural damage, modulates gene expression, and promotes autophagy; the in vivo arm of the research, however, did not reveal resveratrol to have appreciable antiparasitic activity [198].

3.2. Antiparasitic Activity Against Hymenolepis diminuta

Hymenolepis diminuta, the rat tapeworm, infects humans in tropical regions with poor sanitation [224]. Infections are rare and usually affect children [225,226]. Praziquantel is the drug of choice, but there are still gaps in the understanding of the epidemiology and pathophysiology of the disease [227]. The extract from Carex baccans was found to reduce the worm burden in infected rats, and resveratrol, when isolated further, was equally effective. Due to their good tolerance and effectiveness, they seem promising potential antiparasitic solutions [199].

3.3. Antiparasitic Activity Against Naegleria fowleri

Naegleria fowleri is a free-living parasite that can complete its life cycle outside of a host [228,229]. It causes primary amoebic meningoencephalitis, which is often fatal [229,230,231]. Infection occurs in freshwater via the nasal passages, and the treatment is difficult, owing to a lack of widely tried therapies and problems in timely diagnosis. The current treatment regimen comprises a host of drugs, namely amphotericin B, azithromycin, fluconazole, rifampin, dexamethasone, and miltefosine, but the scheme has unreliable efficiency and high toxicity [232,233].

Piceid was amongst the most effective phytochemicals isolated from Gossypium hirsutum, i.e., cotton plant, and tested in silico for effectiveness against N. fowleri. Based on molecular docking studies, piceid was found to obey all the rules for drug likeness against which it was tested and, importantly, showed good gastrointestinal absorption. Therefore, it is a promising candidate for an S-adenosyl-L-homocysteine hydrolase inhibitor, which is a basic metabolic enzyme of the parasite [200].

3.4. Antiparasitic Activity Against Leishmania spp.

Leishmaniasis is endemic in tropical and subtropical regions and is mostly transmitted through sand flies [234]. It presents with a variety of symptoms and can have several clinical forms [235]. Over 20 different species of Leishmania are infectious, and transmission vectors persist in different areas, despite efforts at eradication [236]. The current regimen of antileishmanial drugs is based on antimonials, which, while effective, have significant adverse effects and are associated with increasing resistance [237,238,239].

Piceatannol proved to be moderately effective against the extracellular forms of L. donovani, L. infantum, and L. major, but was more active than the reference compound in the extracellular form of L. donovani [84]. In the more recent experiments of Passos et al. [202], in mice, it proved to be effective against both the amastigote and promastigote stages of L. amazonensis, with an IC₅₀ far lower than the toxicity limit for healthy cells. Pterostilbene was found to be effective against amastigote and promastigote stages of L. amazonensis, but could not alter its cell cycle, in contrast to piceatannol; it was found to decrease the production of pro-inflammatory mediators in infected macrophages and reduce NO levels [202].

Resveratrol was shown to be potent against L. major against promastigotes and intracellular amastigotes, although the mechanism of its action was not elucidated [205]; another research effort some years later confirmed its antileishmanial activity in vitro, noting that it was most probably a result of its cytotoxicity against host cells, rather than a direct antiparasitic action [206]. Against L. amazonensis, resveratrol exhibited a synergistic effect with amphotericin B, resulting in inhibition of proliferation and incidental parasite death [201]. Another team performed molecular and computational docking studies to explore the effects of resveratrol and some of its analogues in trypanothione reductase, the enzyme that is associated with resistance to miltefosine and pentavalent antimonials [240]; it was found that these compounds could effectively inhibit the enzyme, and the analogues displayed better GIT absorption potential [204]. Resveratrol analogues in vitro were found to exert their antileishmanial effects via a multitude of mechanisms, with potential comparable to current antileishmanial agents [203]. Finally, the antiparasitic potential of resveratrol against L. major was demonstrated both in vivo and in vitro by [207].

3.5. Antiparasitic Activity Against Plasmodium falciparum

Plasmodium falciparum is one of the five species of the genus Plasmodium, the causative agent of malaria [241]. Malaria is responsible for about half a million deaths annually, and causes considerable morbidity even in surviving patients [242]. There is an evident need for alternative treatment strategies due to the adverse effects and emerging resistance patterns of current agents [243]. Resveratrol and piceid, along with other derivatives, were found to be effective against Plasmodium falciparum in vitro, following a spectroscopic determination of their structures [208].

3.6. Antiparasitic Activity Against Schistosoma mansoni

Schistosomiasis is the helminthic human disease with the highest morbidity and mortality [244,245,246,247], and in spite of increased efforts of vector eradication or infection prevention [248], it remains a significant health problem in certain African regions [249,250] even re-emerging in Southern Europe [251].

The current core treatment for schistosomiasis comprises only praziquantel [249], which is increasingly associated with lower cure rates, potentially associated with emerging resistance to the drug [252,253]. Therefore, the need for novel treatment strategies is urgent. Based on this, Gouveia et al. [209] tested resveratrol and N-acetylcysteine against S. mansoni, alone or combined with antihelminthic drugs. Praziquantel and resveratrol and artesunate and resveratrol displayed moderate and good synergies, respectively, and further research on their anti-schistosomal potential seems promising [209].

3.7. Antiparasitic Activity Against Toxoplasma gondii

This pathogen causes human toxoplasmosis, a disease affecting a significant percentage of the population but that is usually clinically insignificant; infection usually happens by consuming undercooked meat [254]. Toxoplasmosis is particularly dangerous for pregnant women and for newborns in cases of vertical transmission [255]. In immunocompromised individuals, it may even progress to toxoplasmic encephalitis [256]. The principal treatment agents are dihydropteroate synthetase and dihydrofolate reductase inhibitors [257], but the treatment is ineffective regarding oocysts eradication [254].

Piceatannol was found to be effective against the T. gondii both in vitro and in vivo; it proved effective in both cases, in the latter against a tachyzoite stage infection in mice, even though its effectiveness was limited as the mice died by day 15 [211]. A later study found that it was effective in vitro with no cytotoxicity, but in vivo, it just prolonged the mice’s lifespan, and they eventually died [212].

Resveratrol, in combination with sulfamethoxazole-trimethoprim, was found to exert a protective effect on the host organism from the biochemical changes induced by the drugs, while their antiparasitic effectiveness was retained [210]. Resveratrol on its own was identified to exert both direct and indirect anti-tachyzoite effects in the experiments of [213].

3.8. Antiparasitic Activity Against Trichinella spiralis

T. spiralis is one of the most important foodborne parasites, causing trichinellosis [258]. The disease is contracted from improperly cooked meat, most commonly pork or wild game, and is potentially fatal [259]. The larvae mature in the intestines and disseminate via the bloodstream to encyst within striated muscle tissue, causing a variety of clinical manifestations [260]. Albendazole and mebendazole are current treatments that face limitations in certain population subgroups and may also prove ineffective in severe cases [260]. Resveratrol was found to inhibit different stages of T. spiralis, at different concentrations, with higher concentrations being more effective [214].

3.9. Antiparasitic Activity Against Trypanosoma cruzi

Trypanosoma cruzi is the etiological agent of Chagas disease, a neglected tropical disease, which has worldwide dispersion and global health impact [261]. Chagas disease has a clinically silent acute phase, but about 30% of patients progress to the potentially fatal chronic phase [262]. The current treatment, consisting of nifurtimox and benznidazole, requires chronic administration, carries toxic side effects, and suffers from reduced efficacy [263].

Campo [217] found that resveratrol strongly inhibited parasite replication after 48 h incubation. Resveratrol also selectively altered trypomastigote transcription levels and surface protein expression. One year earlier, the molecular docking of resveratrol in trypanosomal arginine kinase was investigated, and it was found that by inhibiting this enzyme, resveratrol could inhibit the activity of different trypanosomal stages [216]. In the same year, the administration of resveratrol for 30 days in rats, with chronic chagasic cardiomyopathy, was found to exert a cardioprotective and restorative effect, representing a potential starting point for novel treatments [215].

4. Antiviral Potential of Stilbenoids Against DNA Viruses

DNA viruses are generally large viruses, which may cause significant morbidity if left untreated [264,265]. While for many of these viruses there exist efficient treatment schemes or vaccines [266,267], the quest for novel therapeutic solutions is important in the context of emerging resistance and potential side effects of antiviral drugs [268,269]. In general, there are ample data documenting the antiviral effects of stilbenoids against DNA viruses (Table 5).

Table 5. Available data on the antiviral potential of the main stilbenoids against DNA viruses, organized alphabetically by family and species, and then chronologically (potency reported as per the original research).

Family	Species	Study Type	Compound	Extract from	Concentration	Mechanism	Year	Reference
Hepadnaviridae	Hepatitis B virus (HBV)	In vitro	Pterostilbene	Pure compound	1.45 μg/mL (EC50)	Inhibition of viral replication; inhibition of infected cell proliferation	2021	[270]
		In vitro	Resveratrol	Pure compound	11.41 μg/mL	Inhibition of viral replication; reduction in cytotoxicity in infected cells	2022	[271]
		In vivo			100 mg/kg/day	Decrease in serum DNA in mice
Orthoherpesviridae	Cytomegalovirus (CMV)	In vitro	Resveratrol	Pure compound	0.23–0.46 μg/mL (IC50)	Inhibition of viral replication; inhibition of virus-induced cellular signaling	2004	[272]
		In vitro	Piceatannol	Pure compound	0.24–12.21 μg/mL	Inhibition of viral replication; suppression of mechanisms of cellular senescence	2020	[273]
		In vitro	Pterostilbene	Pure compound	0.34 μg/mL (IC50)	Inhibition of cell lysis; inhibition of viral protein expression; suppression of viral replication	2022	[274]
	Duck enteritis virus (DEV)	In vitro	Resveratrol	Pure compound	3.85 μg/mL (IC50)	Inhibition of viral replication proteins	2013	[275]
	Epstein–Barr virus (EBV)	In vivo	Resveratrol	Pure compound	16.38 ± 0.45 μg/mL (IC50)	Inhibition of early antigen activation; free radical scavenging	2002	[276]
		In vitro	Resveratrol	Pure compound	11.91 μg/mL (EC50)	Reduction in virion production	2010	[277]
		In vitro	Resveratrol	Pure compound	Different EC50 for different cell lines	Cell cycle arrest and apoptosis in infected cells	2011	[278]
		In vitro	Resveratrol	Pure compound	Different concentrations depending on cell line and protocol	Inhibition of viral protein expression; suppression of redox-sensitive transcription factors	2012	[279]
		In vitro	Resveratrol	Pure compound	5.71 and 11.41 μg/mL	Anti-apoptotic effect of infected cells	2012	[280]
	Herpes simplex virus (HSV)	In vitro	Resveratrol	Pure compound	50 μg/mL	Inhibition of viral replication and reactivation	1999	[281]
		In vivo	Resveratrol	Pure compound	12.5 or 25% resveratrol cream	Suppression of lesion formation	2004	[282]
		In vivo	Resveratrol	Pure compound	19% resveratrol cream	Reduction in viral replication and limitation of disease spread	2005	[283]
		In vitro	Resveratrol	Pure compound	50 μg/mL	Suppression of NF-κB activation; inhibition of viral genome expression and replication	2006	[284]
		In vitro	Resveratrol	Pure compound	6.85 μg/mL	n/a (only resveratrol derivatives were effective)	2012	[285]
	Pseudorabies virus (PRV)	In vitro	Piceatannol	Pure compound	30.7 μg/mL (IC50)	Inhibition of viral replication; inhibition of infected cell apoptosis	2023	[286]
		In vivo			50 mg/kg per day	Protective effect (reduction in viral load)
	Varicella–Zoster virus (VZV)	In vitro	Resveratrol	Pure compound	50 μg/mL	Inhibition of viral replication	2006	[287]
Polyomaviridae	Polyomaviruses	In vitro	Resveratrol	Pure compound	4.56 and 5.71 μg/mL	Inhibition of viral DNA synthesis	2009	[288]

4.1. Antiviral Activity Against Hepatitis B Virus (HBV)

This pathogen is transmitted via blood and bodily fluids [289,290]. Infection with the virus is associated with significant mortality all over the world [289,290,291], as it causes liver dysfunction [292], which can even progress to chronic hepatitis [289,291,292], with pregnant women and children accounting for the main risk groups [289,293]. There is a vaccine, as well as several pharmaceutical substances, which are used to avoid or manage the condition, respectively [289,292,293], and have proven successful to a large degree.

Pterostilbene was found to be able to inhibit the activity of the virus’s ribonucleotide reductase in vitro—the IC₅₀ being about 0.62 μM—by interacting with protein RRM2 [270]. In addition, it managed to inhibit cell proliferation at an IC₅₀ of 20–40 μM in several HCC cell lines, inhibiting DNA synthesis, inducing cell cycle arrest at S phase, and eventually leading to apoptosis. Moreover, it inhibited viral DNA replication in HBV genome-integrated and newly transfected HCC cells [270]. Interestingly, the EC₅₀ for inhibiting HBV replication was notably lower than the IC₅₀ for inhibiting HCC proliferation [270]. It is worth mentioning that pterostilbene exerted comparable inhibitory effects even in sorafenib and lamivudine-resistant HCC cells [270]. Furthermore, pterostilbene effectively inhibited xenograft growth of HCC in nude mice without causing significant toxicity [270].

Based on the research of Pan et al. [271], 50 μM of resveratrol was sufficient to markedly inhibit viral replication and reduce cytotoxicity in HepG2 and HepG2.2.15 cell lines. This was attributed to inhibition of miR-155 expression and increased autophagy [271]. Resveratrol’s effectiveness against this pathogen extends in vivo, as 100 mg/kg/day was capable of significantly decreasing viral DNA levels in the serum of infected mice [271].

4.2. Antiviral Activity Against Cytomegalovirus (CMV)

This virus is an important cause of congenital infections, potentially leading to a multitude of disabilities [294,295], be they intellectual, neurological, developmental, acoustic, or ocular [295]. In the pediatric population, this pathogen is also commonly linked to Ménétrier’s disease [296]. There are cases where the virus displays resistance to pharmacological agents used against it, although the preventive action of letermovir and ganciclovir remains efficacious [297].

Piceatannol exerted inhibitory effects when tested against this pathogen in vitro by preventing lytic changes, reducing viral protein expression and viral DNA replication in a dose-dependent manner, and decreasing SA-β-Gal (senescence-associated β-galactosidase) activity as well as the amount of intracellular ROS; the associated quantity was 10 or 20 μM depending on the extent of the effect [273]. Overall, these findings suggest that piceatannol could be useful in dealing with patients suffering from chronic CMV infection [273].

Pterostilbene can also prevent lytic changes, inhibit viral protein expression, and suppress the replication of viral DNA, bringing about a notable reduction in viral titer in WI-38 cells at an IC₅₀ of 1.315 μM [274]. In addition, HCMV infection-caused cell senescence was suppressed due to the presence of pterostilbene, as indicated by the decreased values of the relevant markers. Most worthy of note are the decrease in production of ROS and in the activity of senescence-associated β-galactosidase [274]. Overall, pterostilbene mostly acts after the virus makes its way into the cell via membrane fusion [274].

Resveratrol was also able to inhibit viral replication at an IC₅₀ of 1–2 μM when tested on HEL 299 cells, while a minimum 50-fold higher concentration had to be applied before cytotoxic effects were exerted on healthy cells [272]. Notably, viral DNA replication and the late phases of virus-induced phosphatidylinositol-3-kinase signaling and transcription factor activation reached undetectable levels [272]. It was deduced that if applied before four hours post-infection, resveratrol can block virus-induced epidermal growth factor receptor activation, phosphatidylinositol-3-kinase signal transduction, and NF-kappaB and Sp1 transcription factor activation [272]. Thus, the compound probably acts during attachment and entry to host cells [272].

4.3. Antiviral Activity Against Epstein–Barr Virus (EBV)

This virus has been linked to various types of malignancy [298,299,300,301]—most notably Burkitt’s lymphoma, autoimmune conditions—namely SLE (systemic lupus erythematosus) [302,303], and very recently, it has even been implicated in the pathogenesis of thyroid conditions such as Graves’ disease and Hashimoto thyroiditis [299].

Resveratrol has proven its antitumoral potential against this pathogen both when tested in vitro and in vivo [276]. When tested in P3HR1 cells, it was able to inhibit the expression of the immediate-early proteins Rta, Zta, and EA-D at an EC₅₀ of about 24 μM, without any cytotoxicity being recorded below 55 μM [277]. Inhibition was also noted at the level of the transcriptional activity of the promoters BRLF1 and BZLF1, accompanied by a reduced production of mature viral particles, the EC₅₀ for this to occur being 52.2 μM [277]. Similarly, 25 μM of resveratrol in human B cells inhibited viral transformation by more than 70% [280]. At 50 μM, this amount was increased to more than 95% [280]. The inhibition and decreased survivability of the transformed cells were made possible by resveratrol downregulating the anti-apoptotic proteins Mcl-1 and survivin, as a result of suppressing NFκB and STAT-3 signaling pathways, and of reducing the expression of LMP1, an oncogenic viral product [280]. Adding to this, the compound led to reduced expression of miR-155 and miR-34a in infected cells and prevented the expression of BHRF1, an anti-apoptotic viral gene [280]. Comparably, [278] concluded that resveratrol can induce apoptosis in Burkitt’s lymphoma cells by inducing phosphorylation of p38 MAPK and suppressing the ERK1/2 signaling pathway.

Expanding on this, testing conducted on two Burkitt’s lymphoma cell lines led to the realization that resveratrol is a potent inhibitor of the initiation of the lytic cycle [279]. Importantly, resveratrol was able to inhibit the expression of lytic genes, as well as the production of viral particles, in cross-linked Akata cells, a system of Epstein–Barr induction that probably bears a strong resemblance to the in vivo model of the virus’s reactivation [279]. In Raji cells, this property was attributed to its ability to cause ectopic expression of the immediate-early gene BZLF1, while in the case of the Akata cells, to the activation of the B-cell receptor signaling pathway [279]. A decrease in ROS production and in the transcription of factors NF-κΒ and AP1 was also noted [279]. Likewise, when applied to infected Raji cells, resveratrol caused a 57.2% inhibition of early antigen activation at a concentration of 100 times the molar ratio to TPA, while at the maximum tested concentration, early antigen activation was reduced to 8.2 ± 0.4% [276]. During the tests that were conducted on mice with skin papillomas, gross tumor incidence was reduced to 20% after topical application, while 20 weeks post-treatment, tumor incidence was inhibited by more than 30% [276]. These effects can be attributed to a variety of mechanisms, such as resveratrol’s antioxidant and cytotoxic properties [276].

4.4. Antiviral Activity Against Herpes simplex Virus (HSV)

The serotypes HHV-1 and HHV-2 have a great range of geographical distribution [304,305], involving facial and/or genital lesions [304,305,306,307]. The spread of the infection to a neonate is possible and a cause for concern [308]. Fortunately, the use of acyclovir has been instrumental in handling these pathologies, while vaccines utilizing nanoparticles are in development [309].

During tests conducted on Vero cells, resveratrol was found to inhibit herpes simplex virus at 50 μg/mL by acting early during its replication cycle, as well as delay the cell cycle at S-G2-M interphase, inhibit reactivation from latently infected neurons, and decrease the amount of the immediate-early regulatory protein ICP-4 [281]. The research of Faith et al. [284] corroborates these findings; at 219 μM, resveratrol was able to inhibit viral replication in Vero cells during their tests by suppressing the activation of NF-κB, and reducing mRNA for ICP0, ICP4, ICP8, as well as the virus’s DNA polymerase. Correspondingly, α-Viniferin, a resveratrol trimer, exhibited antiherpetic activity in vitro at an IC₅₀ of 27.4 ± 0.5 μΜ for HSV-1 and 4.2 ± 0.4 μΜ for HSV-2 [285]. Resveratrol was also active on this pathogen when topically applied several times over a few days in infected SKH1 mice as 12.5% and 25% cream [282]. However, for lesion suppression to occur, these creams had to be applied earlier than 12 hours post-infection [283]. Importantly, resveratrol’s effectiveness was the same as that of acyclovir, but it was also active when tested against an HSV-1 acyclovir-resistant strain [283]. Likewise, resveratrol creams applied several times per day in murine lesions, both vaginal and extravaginal, showed variable degrees of effectiveness depending on the formulation, with comparable efficacy limitations being imposed by similar delays in post-infection application [283]. Overall, the 19% resveratrol cream was the most potent [283]. Even though the decrease in morbidity and mortality is indisputable, the details of the mechanism behind it have yet to be elucidated [283].

4.5. Antiviral Activity Against Polyomaviruses

SV40, the archetypal virus of this category, has seen extensive use as a model system to broaden our understanding of fundamental eukaryotic cellular processes [310]. There is a link between polyomaviruses and malignancy [310], such as in the case of Merkel cell carcinoma [311]. Other notable pathologies include transplant-related kidney disease, usually caused by BKPyV and JCPyV, and progressive multifocal leukoencephalopathy, a serious condition that is occasionally encountered in immunosuppressed patients and is associated with JC infection [312]. When applied to HL60, a human promyelocytic leukemia cell line, resveratrol managed to notably inhibit cell growth at 25 μM [288]. In addition, at a concentration of 20 μM, viral replication was brought to a halt [288].

4.6. Antiviral Activity Against Varicella–Zoster Virus (VZV)

Varicella–Zoster virus is the causative agent for varicella (chickenpox) and herpes zoster (shingles) [313]. Primary infection is followed by lifelong latency with subsequent reactivations, particularly in immunocompromised individuals, and can lead to neuralgia or other neurological sequelae [314,315]. Pathogenesis is characterized by cell-to-cell spread and neurotropism, and the virus possesses the ability to evade the host immune responses [315]. Vaccination, both for the pediatric population and the elderly, has the potential tto limit the pathogen’s impact, but the disease burden remains substantial [316,317]. Resveratrol can inhibit this pathogen’s replication in a dose-dependent manner; at 219 μM, where no toxicity for healthy cells was noted, the synthesis of the immediate-early viral protein IE62 was diminished 72-fold [287]. However, for this effect to be exerted, it had to be administered within 30 hours post-infection [287].

5. Antiviral Potential Against RNA Viruses

In general, RNA viruses are associated with a significant burden of disease and represent a significant strain on health systems worldwide. For a number of reasons, certain RNA viruses are associated with persistence [318]. While there have been significant breakthroughs in the elucidation and understanding of the processes involved in related infectious disease pathogenesis and transmission [319], resistance to antiviral agents complicates drug discovery [320]. The stilbenoids discussed herein have been tested against RNA viruses (Table 6) and may prove invaluable in addressing some of the existing or emerging therapeutic challenges.

Table 6. Available data on the interaction of the stilbenoids discussed in the text with RNA viruses, organized alphabetically by family and species, and then chronologically (potency reported as per the original research).

Family	Species	Study Type	Compound	Extract from	Concentration	Mechanism	Year	Reference
Coronaviridae	SARS-CoV2	In vitro	Pterostilbene	Pure compound	4.87 μg/mL (EC50) and 12.05 μg/mL (EC90); different concentrations in different experiment types	Inhibition of viral replication inside infected cells	2021	[321]
		In vitro	Resveratrol	Pure compound	15.06 μg/mL (EC50) and 27.16 μg/mL (EC90); different concentrations in different experiment types	Inhibition of viral replication inside infected cells
		In vitro	Resveratrol	Pure compound	1.05 μg/mL (EC50)	Inhibition of viral replication inside infected cells	2021	[322]
		In vitro	Piceid	Reynoutria japonica, Reynoutria sachalinensis	n/a (IC50 available for all fractions)	Weak Mpro inhibition	2021	[323]
Flaviviridae	Hepatitis C virus (HCV)	In vitro	Resveratrol	Pure compound	n/a (no antiviral effect)	Promotion of viral DNA replication *	2010	[324]
Orthomyxoviridae	Influenza virus	In vitro	Resveratrol	Pure compound	40 μg/mL (for total inhibition of replication)	Inhibition of viral replication inside infected cells	2005	[325]
		In silico	Piceid	Pure compound	n/a (molecular docking study)	Inhibition of viral neuraminidase	2013	[326]
		In vitro	Piceatannol	Pure compound	n/a	Rupture of the viral envelope and inactivation of viral particles; blockade of membrane fusion and of conformational change in hemagglutinin	2023	[327]
		In vivo				Reduction in viral titers and promotion of survival
		In vitro	Pterostilbene	Pure compound	5.13 μg/mL	Inhibition of viral replication	2023	[328]
		In vivo	Pterostilbene	Pure compound	30 or 60 mg/kg per day	Suppression of inflammation and apoptosis; preservation of epithelial cell integrity; modulation of macrophage polarization	2024	[329]
Picornaviridae	Human enterovirus	In vitro	Resveratrol	Pure compound	30 μg/mL	Inhibition of viral replication and pro-inflammatory cytokine secretion	2015	[330]
		In vitro	Pterostilbene	Pure compound	3.25 μg/mL (EC50) (different results for different viral strains)	Inhibition of progeny virus; inhibition of viral replication; inhibition of viral protein production; inhibition of enteroviral attachment	2025	[331]
		In vivo			50 mg/kg	Increase in survival rate; improved disease outcomes (potential stimulation of innate immunity)
	Human rhinovirus	In vitro	Resveratrol	Pure compound	68.47 μg/mL	Inhibition of viral replication; inhibition of pro-inflammatory factors secretion	2015	[332]
	Theiler’s murine encephalomyelitis virus (TMEV)	In vivo	Resveratrol	Pure compound	20 mg/kg/day	Significant increase in demyelination and inflammation without neuroprotection of the central nervous system *	2013	[333]
Pneumoviridae	Human metapneumovirus	In vitro	Resveratrol	Pure compound	2.28–11.41 μg/mL	Inhibition of viral replication; reduction in cellular oxidative damage; reduction in inflammation	2015	[334]
	Respiratory syncytial virus (RSV)	In vivo	Resveratrol	Pure compound	30 mg/kg per day	Reduction in viral titers, lymphocyte infiltration, inflammation and interferon production	2011	[335]
		In vitro	Resveratrol	Pure compound	Different concentrations depending on experimental protocol	Decrease in IL-6 production and partial inhibition of viral replication	2012	[336]
		In vivo	Resveratrol	Pure compound	30 mg/kg/day	Increase in pro-inflammatory cytokine secretion (TNF-α, IFN-γ, and IL-2)	2014	[337]
		In vivo	Resveratrol	Pure compound	30 mg/kg/day	Downregulation of MMP-12 and interferon production	2015	[338]
		In vivo	Resveratrol	Pure compound	30 μg/mL	Suppression of persistent airway inflammation	2015	[339]
Retroviridae	Human immunodeficiency virus (HIV)	In vitro	Resveratrol	Pure compound	1.32 μg/mL (EC50)	Inhibition of HIV-1 strains replication	2014	[340]

* Not an antiviral mechanism.

5.1. Antiviral Activity Against SARS-CoV-2

This highly contagious virus belongs to the Coronaviridae family and causes coronavirus disease 2019 (COVID-19) [341]. Its spike glycoprotein interacts with the angiotensin-converting enzyme 2 receptor, facilitating viral entry and replication [342]. The clinical manifestations can include severe pneumonia, acute respiratory distress syndrome, and multisystem involvement, more often in immunocompromised and elderly patients [343,344,345].

Pterostilbene inhibits infection of Vero cells by this pathogen, reducing viral particle production by 50% at 19 µM, although it exerted no notable effects on infected Calu-3 cells [321]. Importantly, pterostilbene can inhibit SARS-CoV-2 infection in primary human bronchial epithelial cells cultured under ALI (Air–Liquid Interface) conditions to a great extent [321]. Pterostilbene seems to interfere with viral replication after the pathogen enters the cell, but before the assembly and release of virions take place [321].

Resveratrol also inhibits infection of Vero cells by this pathogen, the reduction in viral particle production reaching 50% at 66 µM, although it also exerted no notable effects on infected Calu-3 cells [321]. Importantly, resveratrol can inhibit SARS-CoV-2 infection in primary human bronchial epithelial cells cultured under ALI (Air–Liquid Interface) conditions to a great extent [321]. Similarly, [322] noticed that resveratrol decreased the viral titer by 80% in MRC5 cells, recording an EC₅₀ of 4.6 µM, with cytotoxicity being kept at a minimum. Resveratrol seems to interfere with viral replication after the pathogen enters the cell, but before the assembly and release of virions take place [321]. However, it has poor affinity for Mpro [323]. Piceid can also bind to Mpro, albeit weakly, making it not really effective as an anti-coronavirus agent [323].

5.2. Antiviral Activity Against Hepatitis C Virus

Infection with this pathogen can be lethal as it can cause cirrhosis [346] and hepatocellular carcinoma, especially in patients with persistent viraemia [347,348]. While direct-acting antivirals improved cure rates, there are still challenges related to viral resistance, reinfection, and access to treatment [346]. Interestingly, resveratrol was noted to markedly increase the replication of the virus’s RNA and even reverse the effects of ribavirin and interferon against it. Therefore, it cannot be considered a suitable antioxidant therapy in the case of HCV infection. [324].

5.3. Antiviral Activity Against Influenza Virus

This highly contagious pathogen mainly affects the respiratory system [72] and is often implicated in pandemics [349]. Due to the resistance it has developed to some of the agents used against it [349,350], as well as its antigenic shift and antigenic drift traits [351], the latter of which necessitates yearly vaccine updates [352], it poses a challenge for the health system.

Piceatannol has potent anti-influenza effects in vitro, but also in vivo [327]. It can inhibit the multiplication of H1N1 and H3N2 viruses, while also preventing infection with H5N1 pseudovirus, with low toxicity. Piceatannol blocks membrane fusion while also possibly acting on the virus’s envelope. Moreover, mice that received piceatannol orally displayed reduced viral titers and notably improved survival rates [327].

Pterostilbene was shown to interact with influenza NS1 protein, inhibiting ubiquitination-mediated degradation of RIG-I, and activating the downstream antiviral pathway, thereby promoting an antiviral state at 200 μM in A549 cells [328]. Pterostilbene’s efficacy was also exhibited in vivo, as it managed to reduce histopathological changes at the level of the lungs in mice [329]. This was made possible due to the activation of the phosphorylated AMP-activated protein kinase alpha/sirtui 1/PPARγ coactivator-1α axis, which counteracted the nuclear factor kappa-B and p38 mitogen-activated protein kinase signaling, which is caused by the virus [329]. In a similar vein, pterostilbene can counteract the virus-mediated M1 macrophage polarization [329]. Finally, it seems to suppress pro-inflammatory mediators and proapoptotic factors [329].

Resveratrol can also be useful against influenza, both in vitro and in vivo [325]. It can cause a 90 ± 2.5% inhibition of viral replication in MDCK cells at 20 mg/mL, which becomes total at 40 mg/mL, by blocking the nuclear-cytoplasmic translocation of viral ribonucleoproteins and decreasing expression of late viral proteins, probably through inhibition of the activity of protein kinase C and its dependent pathways [325]. When it comes to infected mice, there was a notable increase in survival and a notable decrease in pulmonary viral titers [325]. Importantly, there were no toxic effects in either case [325]. The fact that resveratrol’s action is exerted on a cellular function, and not a viral one, presents positive implications regarding its effectiveness as a drug [325]. Finally, piceid was found to be potent against the virus’s NA by docking into the active site of N1 during testing in silico [326].

5.4. Antiviral Activity Against Human Enteroviruses (HEVs)

The enterovirus genus comprises several viral pathogens, most notably enterovirus 71, enterovirus D68, and Coxsackie virus [353]. HEVs are responsible for a variety of manifestations, ranging from self-limited illnesses such as hand, foot, and mouth disease, or upper respiratory infections, up to encephalitis, myocarditis, meningitis, or acute flaccid paralysis [354,355,356,357].

Pterostilbene is potent against enteroviruses both in vitro and in vivo [331]. On one hand, it is capable of inhibiting viral attachment to a great degree, inactivating viral particles, blocking viral binding to the receptors, and increasing virion stability [331]. By occupying a hydrophobic pocket in viral protein 1, owing to its strong binding affinity, it acts as a potent inhibitor [331]. On the other hand, oral intake of pterostilbene ameliorated infection-related symptoms and reduced mortality in hSCARB2 transgenic mice [331].

Resveratrol is highly effective against enterovirus 71 due to its ability to inhibit the synthesis of VP1, a capsid protein, while also having an anti-inflammatory role by preventing the phosphorylation of IKKα, IKKβ, IKKγ, IKBα, NF-κB p50, and NF-κB p65 [330]. In addition, the marked upregulation of IL-6 and TNF-α in EV71-infected rhabdosarcoma cells was blocked by the compound. These effects were exerted at 30 μg/mL of resveratrol [330].

5.5. Antiviral Activity Against Human Rhinovirus

This virus is commonly implicated in cases of acute viral respiratory infections [358,359,360], but it can also negatively affect the progression of chronic pulmonary conditions such as asthma and COPD [358]. The resulting morbidity can be significant, with children occasionally requiring admission to the ICU and older adults requiring oxygen support [359].

Application of 300 μM of resveratrol on H1HeLa cell monolayers and ex vivo nasal epithelia resulted in potent RSV-16 replication inhibition, as well as diminished secretion of IL-6, IL-8, and RANTES, leading to a less pronounced inflammatory response, without any display of cytotoxicity [332]. Furthermore, the upregulated expression of ICAM-1 by the virus was counteracted by resveratrol [332].

5.6. Antiviral Activity Against Theiler’s Murine Encephalomyelitis Virus (TMEV)

This virus determines encephalomyelitis and chronic demyelinating disease in rodents [361,362]. Since the demyelination it causes resembles that of multiple sclerosis, it is used as a viral model in the study of that pathology [362]. Interestingly, resveratrol was found to exacerbate the demyelination caused by the pathogen when tested in vivo, with the inflammation having a notably increased intensity [333].

5.7. Antiviral Activity Against Human Metapneumovirus

This pathogen causes symptoms such as cough, sore throat, and fever [363,364], but it can also cause acute respiratory distress syndrome, especially in children, the elderly, and the immunocompromised [364,365]. Regrettably, its role is still largely underestimated [363].

When resveratrol was applied to airway epithelial cells, cellular oxidative damage was reduced [334]. Moreover, the production of inflammatory mediators, as well as their viral replication, was decreased. The anti-inflammatory effects were exerted by inhibition of NF-κB and IRF-3 [334]. Since viral gene transcription and protein synthesis remained intact, the inhibition of viral replication is considered to have taken place during viral assembly, release, or both [334].

5.8. Antiviral Activity Against Respiratory Syncytial Virus (RSV)

RSV is a leading cause of acute lower respiratory tract infections worldwide, affecting primarily infants and young children [366]. Fusion and attachment glycoproteins mediate viral entry and spread [367]. With limited therapeutic options, RSV remains a major target for novel antiviral compounds despite recent advances in vaccines and monoclonal antibodies [368].

At 50 μM, resveratrol decreased the level of IL-6 in infected 9HTEo cells, although not that of IL-8, resulting in a milder inflammatory response [336]. This was associated with suppression of the activation of NF-κB by TRIF and TBK1, and of the expression of RIP-1, both of which the pathogen normally upregulates [336]. At an optimal concentration of 100 μM, the compound was also able to reduce viral titers in both 9HTEo cells and Hep-2 cells [336]. When administered to BALB/c mice at 30 mg/kg/day, resveratrol was shown to notably reduce interferon-γ production, although not any of the other associated cytokines, thereby decreasing the levels of airway inflammation; the amount of lymphocyte-rich infiltrates and tissue damage was markedly diminished [335]. These findings are in accordance with those of Liu et al. [369], who also noticed diminished inflammation intensity in BALB/c mice due to reduced interferon-γ levels, as a result of SARM upregulation and TRIF downregulation. The same is true of the tests that were carried out by Long et al. [338]; both BALB/c mice and nude mice benefited from anti-inflammatory effects following resveratrol administration due to MMP-12 downregulation, with the former also experiencing a decrease in interferon-γ production. In a similar vein, resveratrol seems to reduce the levels of NGF, thereby suppressing persistent airway inflammation in mice [339]. Interestingly, when administered to SD mice at 30 mg/kg/day via retention enema, resveratrol was shown to boost the inflammatory response against the pathogen by upregulating TNF-α, IL-2, IFN-γ, and SIgA [337].

5.9. Antiviral Activity Against Human Immunodeficiency Virus (HIV)

HIV is the causative agent of acquired immune deficiency syndrome (AIDS), and primarily targets CD4⁺ T cells, macrophages, and dendritic cells, leading to progressive immune dysfunction and higher susceptibility to infections or malignancies [370,371]. Antiretroviral therapy has seen major advances, but drug resistance, viral latency, and lack of a curative strategy still motivate the search for novel antiviral compounds [372,373].

Resveratrol was found to inhibit HIV-1 strains that carry the M184V mutation in reverse transcriptase by interfering with DNA synthesis when tested in peripheral blood lymphocytes, the associated EC₅₀ being 5.8 μM, although it was not active on the wild type of the virus [340].

6. Discussion

Stilbenes have a host of beneficial health properties, including antioxidant, anti-inflammatory, and anticancer activity [374,375,376], while analgesic and anti-atherosclerotic properties were also demonstrated [374,375]. We have shown above the extent of their antifungal, antiviral, and antiparasitic roles in humans, and a summary of the mechanisms of action is provided in Figure 2 and reviewed in the following sections.

Figure 2. Synthetic overview of the action mechanisms of stilbenoids against fungi, parasites, and viruses.

6.1. Overview of the Antifungal Properties of Stilbenoids

Based on the results of the research presented in the text, stilbene phytoalexins in most cases efficiently affect fungal growth, or have an otherwise notable antifungal action (Table 7).

Table 7. Synopsis of the antifungal mechanisms of the stilbenoids discussed in the text.

Effect (Mechanism)	Fungi	References
Inhibition of aflatoxin production	A. flavus	[143]
Inhibition of biofilm formation	C. albicans, T. cutaneum	[121,148,150,153]
Disruption of mature biofilm	C. albicans, T. cutaneum	[121,150,153]
Inhibition of fungal growth	A. fumigatus, C. albicans, C. herbarum, T. rubrum	[144,145,147]
Inhibition of mycelial growth	A. flavus	[143]
Fungicidal effect on cells	C. albicans, E. floccosum, M. gypseum, Trichophyton spp., T. beigelii	[146,149,152,377]
Promotion of susceptibility to antifungal agents	C. albicans	[151]

In the majority of antifungal applications, resveratrol has been the most applied stilbenoid, especially in vitro. Older studies identified the antifungal potential of resveratrol [378,379,380,381] and recognized that it, along with other phytoalexins, forms part of the natural defense mechanism of grapevines against fungal infection [382], and against Botrytis cinerea, a notable necrophytic fungus of economic importance in viticulture and horticulture in general [383,384]. There is a corpus of research that directly contradicts the potential of resveratrol against C. albicans, namely that of Docherty et al. [385] and Weber et al. [166].

A particular case concerns the integration of a resveratrol-synthase gene from Polygonum cuspidatum to Arabidopsis thaliana, using parts of a viral vector. The new transgenic plants accumulated trans-piceid, which inhibited Colletotrichum higginsianum colonization [386]. This hemibiotrophic fungus causes anthracnose disease on many cruciferous plants [387]; due to its hemibiotrophic nature, it has developed a range of specialized invasion structures and, as it is a main pathogen of the plant Arabidopsis thaliana, it is one of the best studied fungi of its genus [388].

Candida auris is a novel fungal pathogen that invasively colonizes the skin and thrives on inert surfaces (steel, plastics, etc.), resulting in rapid nosocomial transmission; C. auris has resistance mechanisms to all antifungal classes (azoles, echinocandin, polyene, nucleoside analogues) [389,390]. The biofilm-forming C. auris also has a worrisome ability to survive on surfaces after common hospital disinfectant procedures (sodium hypochlorite, quaternary ammonium, or peracetic acid-based disinfectants) [389,391].

Since biofilm-forming C. auris shares some genetic mechanisms of resistance to antimicrobials with C. albicans [389,391], we propose that an interesting future research avenue would be the quantification of stilbenes’ effects on the C. auris pathogenicity. Currently, there is a lack of experimental data on this issue [392].

6.2. Overview of the Antiparasitic Activity of Stilbenoids

In general, as presented herein, there have been a host of experiments regarding the antiparasitic potential of stilbenoids (Table 8). Resveratrol analogues and derivatives have been tried as antiparasitic agents with different degrees of success [203]. Resveratrol is effective against Echinococcus spp. in vitro, via a variety of mechanisms [198], and it can reduce worm burden in vivo in H. diminuta infections [199]. Against different Leishmania species, it can inhibit proliferation and cause incidental parasite death [201], inhibit trypanothione reductase [204], and promote the death of host cells [206]. Its analogues can disrupt mitochondrial function and lead to membrane permeabilization, and promote autophagic vacuole accumulation [203].

Along with piceid, resveratrol is effective against P. falciparum, although the precise mechanism has not been elucidated [208]; in the same manner, the mechanism of action of resveratrol against T. spiralis is unknown [214]. In the case of T. gondii, resveratrol induces mitochondrial dysfunction, inhibits proliferation, and promotes apoptosis both in infected and host cells [210,211,212,213]. It also exhibits synergistic action with antiparasitic drugs used against S. mansoni [209], and finally, against T. cruzi, resveratrol [215,216,217].

Apart from its direct antiparasitic effects, resveratrol was found to have a protective effect in S. japonicum-induced liver cirrhosis in mice, where it inhibited VEGF expression and reduced oxidative stress [393]. Other research has revealed the effectiveness of resveratrol in parasites that are non-pathogenic to humans, such as Philasterides dicentrarchi [394], but which nonetheless pose a threat to the flora of marine environments [395]. Similarly, resveratrol was found to be effective in inhibiting the energy metabolism of Raillietina echinobothrida, a fowl tapeworm [396]. Moreover, resveratrol was found to be potentially able to inhibit helminth infection-associated carcinogenesis, when combined with other drugs, in individuals infected with Schistosoma haematobium and Opisthorchis viverrine; some metabolites of those parasites are believed to be carcinogenic [397].

Generally, piceatannol is a naturally occurring protein-tyrosine kinase inhibitor [398] which has the potential, either alone or following chemical manipulation, to be of use as an antiparasitic agent against L. amazonensis and L. braziliensis [399]. Its activity against this enzyme was observed in both chloroquine-sensitive and chloroquine-insensitive strains [400]. As such, it may be possible to use it as a substitute for chloroquine, which has the same mode of action, in strains showing resistance, therefore hindering the maturation of the malaria parasite. Early research results had investigated the potential of using piceatannol to inhibit the asexual maturation of P. falciparum [401].

The antileishmanial activity of piceatannol is more or less based on similar mechanisms as that of resveratrol, while pterostilbene exerts cytotoxicity against host cells [202]; other researchers have noted that the antileishmanial potential of piceatannol is associated with its ability to inhibit the parasite’s protein kinase. Piceatannol is also effective against T. gondii, in a manner similar to resveratrol [211,212]. Finally, piceid was recently found to be able to inhibit the S-adenosyl-L-homocysteine hydrolase of N. fowleri [200].

Table 8. Synopsis of the antiparasitic mechanisms of the stilbenoids discussed in the text, organized by parasite.

Parasite	Disease	Vectors	Endemic Areas	Mechanisms of Action	References
Echinococcus spp.	Echinococcosis	Dogs and other canids	Worldwide distribution	Reduction in viability, ultrastructural damage, and increased autophagy gene transcription	[198,218,402]
H. diminuta	Hymenolepiasis	Rats (and other mammals)	Rare (isolated cases)	Reduction in worm burden	[199,403]
N. fowleri	Primary amoebic meningoencephalitis	None	Bodies of warm freshwater	Enzymatic inhibition	[200,404]
Leishmania spp.	Leishmaniasis	Phlebotomous and Lutzomyia sandflies	Africa, Central and South Asia, Central and South America	Inhibition of proliferation and cell cycle progression, incidental parasite death, mitochondrial function disruption, membrane permeabilization, autophagic vacuole accumulation, inhibition of trypanothione reductase, promotion of host cell death, protein kinase inhibition	[84,201,202,203,204,206,405,406,407]
P. falciparum	Malaria	Anopheles mosquitoes	South America, Africa, India, and South Pacific Islands	Unknown mechanism	[208,408,409]
S. mansoni	Schistosomiasis (bilharziasis)	Biomphalaria freshwater snails	Sub-Saharan Africa, South America, Eastern Mediterranean	Synergistic action with antiparasitic drugs	[209,410]
T. gondii	Toxoplasmosis	Cats	Worldwide	Inhibition of parasite proliferation, induction of mitochondrial dysfunction, protective effect for host organism, induction of apoptosis	[210,211,212,213,411]
T. spiralis	Trichinellosis	None specific (undercooked meat)	Worldwide	Unknown mechanism	[214,412]
T. cruzi	Chagas disease	Triatominae insects	Rural areas of South America	Reduction in parasitaemia, cardioprotective effect, arginine kinase inhibition, cell cycle inhibition	[215,216,217,413]

Table 8. Synopsis of the antiparasitic mechanisms of the stilbenoids discussed in the text, organized by parasite.

Parasite	Disease	Vectors	Endemic Areas	Mechanisms of Action	References
Echinococcus spp.	Echinococcosis	Dogs and other canids	Worldwide distribution	Reduction in viability, ultrastructural damage, and increased autophagy gene transcription	[198,218,402]
H. diminuta	Hymenolepiasis	Rats (and other mammals)	Rare (isolated cases)	Reduction in worm burden	[199,403]
N. fowleri	Primary amoebic meningoencephalitis	None	Bodies of warm freshwater	Enzymatic inhibition	[200,404]
Leishmania spp.	Leishmaniasis	Phlebotomous and Lutzomyia sandflies	Africa, Central and South Asia, Central and South America	Inhibition of proliferation and cell cycle progression, incidental parasite death, mitochondrial function disruption, membrane permeabilization, autophagic vacuole accumulation, inhibition of trypanothione reductase, promotion of host cell death, protein kinase inhibition	[84,201,202,203,204,206,405,406,407]
P. falciparum	Malaria	Anopheles mosquitoes	South America, Africa, India, and South Pacific Islands	Unknown mechanism	[208,408,409]
S. mansoni	Schistosomiasis (bilharziasis)	Biomphalaria freshwater snails	Sub-Saharan Africa, South America, Eastern Mediterranean	Synergistic action with antiparasitic drugs	[209,410]
T. gondii	Toxoplasmosis	Cats	Worldwide	Inhibition of parasite proliferation, induction of mitochondrial dysfunction, protective effect for host organism, induction of apoptosis	[210,211,212,213,411]
T. spiralis	Trichinellosis	None specific (undercooked meat)	Worldwide	Unknown mechanism	[214,412]
T. cruzi	Chagas disease	Triatominae insects	Rural areas of South America	Reduction in parasitaemia, cardioprotective effect, arginine kinase inhibition, cell cycle inhibition	[215,216,217,413]

6.3. Overview of the Antiviral Activity of Stilbenoids

Regarding the antiviral effects of stilbenoids discussed in the text, for most of the viruses against which they were tested, they inhibited their replication (Table 9). This is true for all Baltimore Group I viruses, i.e., ASFV, CMV, DEV, EBV, HSV, polyomaviruses, PRV, and VZV. Other molecular mechanisms were also inhibited in certain cases, such as the expression of viral proteins and virus-associated cell signaling. In regard to viral replication, its inhibition has been documented in all tested cases for the other groups, with the exception of HCV and TMEV. For a number of viruses, namely HSV, PRV, human enterovirus, human rhinovirus, HBV, influenza, and RSV, antiviral effects have been recorded in vivo.

We would also like to note that several of the stilbenoids discussed in the text have demonstrated a potent inhibitory activity against HIV-1 integrase and eukaryotic MOS1 transposase [414].

Table 9. Synopsis of the antiviral mechanisms of the stilbenoids discussed in the text, organized by virus; viruses are grouped based on the Baltimore classification [415].

Baltimore Group		Virus	Effect	References
Group I	Double-stranded DNA viruses (dsDNA)	CMV	Inhibition of viral replication; inhibition of virus-associated cellular signaling; suppression of mechanisms of cellular senescence; inhibition of cell lysis; inhibition of viral protein expression	[272,273,274]
		EBV	Inhibition of early antigen activation; free radical scavenging; reduction in virion production; cell cycle arrest and apoptosis in infected cells; inhibition of viral protein expression; anti-apoptotic effect in infected cells	[276,277,278,279,280]
		HSV	Inhibition of viral replication and reactivation; suppression of lesion formation (in vivo); reduction in viral replication (in vivo); inhibition of viral genome expression	[281,282,283,284]
		Polyomaviruses	Inhibition of viral DNA synthesis	[288]
		VZV	Inhibition of viral replication	[287]
Group IV	Positive-sense single-stranded RNA viruses (+ssRNA)	HCV	No significant antiviral effects	[324]
		Human enterovirus	Inhibition of viral replication; promotion of cytokine secretion; inhibition of viral replication; inhibition of viral attachment; inhibition of viral protein production; increase in survival rate (in vivo)	[330,331]
		Human rhinovirus	Inhibition of viral replication; suppression of inflammation	[332]
		SARS-CoV2	Inhibition of viral replication inside infected cells; weal Mpro inhibition	[321,322,323]
		TMEV	No antiviral effect	[333]
Group V	Negative-sense single-stranded RNA viruses (–ssRNA)	Human metapneumovirus	Inhibition of viral replication; reduction in inflammation; reduction in oxidative damage	[334]
		Influenza virus	Inhibition of viral replication inside infected cells; inhibition of viral neuraminidase; inactivation of viral particles; blockade of membrane fusion; reduction in viral titers (& promotion of survival in vivo); immune modulation	[325,326,327,328,329]
		RSV	Reduction in viral titers (in vivo); increase in pro-inflammatory cytokine secretion (in vivo); decrease in interferon and MMP production (in vivo); decrease in interleukin production; inhibition of viral replication; modulation of inflammation (in vivo)	[335,336,337,338,339]
Group VI	Single-stranded RNA viruses with a DNA intermediate in their life cycle (ssRNA-RT)	HIV	Inhibition of viral replication	[340]
Group VII	Double-stranded DNA viruses with an RNA intermediate in their life cycle (dsDNA-RT)	HBV	Inhibition of viral replication; inhibition of infected cell proliferation; reduction in cytotoxicity in infected cells; decrease in serum DNA in mice (in vivo)	[270,271]

Table 9. Synopsis of the antiviral mechanisms of the stilbenoids discussed in the text, organized by virus; viruses are grouped based on the Baltimore classification [415].

Baltimore Group		Virus	Effect	References
Group I	Double-stranded DNA viruses (dsDNA)	CMV	Inhibition of viral replication; inhibition of virus-associated cellular signaling; suppression of mechanisms of cellular senescence; inhibition of cell lysis; inhibition of viral protein expression	[272,273,274]
		EBV	Inhibition of early antigen activation; free radical scavenging; reduction in virion production; cell cycle arrest and apoptosis in infected cells; inhibition of viral protein expression; anti-apoptotic effect in infected cells	[276,277,278,279,280]
		HSV	Inhibition of viral replication and reactivation; suppression of lesion formation (in vivo); reduction in viral replication (in vivo); inhibition of viral genome expression	[281,282,283,284]
		Polyomaviruses	Inhibition of viral DNA synthesis	[288]
		VZV	Inhibition of viral replication	[287]
Group IV	Positive-sense single-stranded RNA viruses (+ssRNA)	HCV	No significant antiviral effects	[324]
		Human enterovirus	Inhibition of viral replication; promotion of cytokine secretion; inhibition of viral replication; inhibition of viral attachment; inhibition of viral protein production; increase in survival rate (in vivo)	[330,331]
		Human rhinovirus	Inhibition of viral replication; suppression of inflammation	[332]
		SARS-CoV2	Inhibition of viral replication inside infected cells; weal Mpro inhibition	[321,322,323]
		TMEV	No antiviral effect	[333]
Group V	Negative-sense single-stranded RNA viruses (–ssRNA)	Human metapneumovirus	Inhibition of viral replication; reduction in inflammation; reduction in oxidative damage	[334]
		Influenza virus	Inhibition of viral replication inside infected cells; inhibition of viral neuraminidase; inactivation of viral particles; blockade of membrane fusion; reduction in viral titers (& promotion of survival in vivo); immune modulation	[325,326,327,328,329]
		RSV	Reduction in viral titers (in vivo); increase in pro-inflammatory cytokine secretion (in vivo); decrease in interferon and MMP production (in vivo); decrease in interleukin production; inhibition of viral replication; modulation of inflammation (in vivo)	[335,336,337,338,339]
Group VI	Single-stranded RNA viruses with a DNA intermediate in their life cycle (ssRNA-RT)	HIV	Inhibition of viral replication	[340]
Group VII	Double-stranded DNA viruses with an RNA intermediate in their life cycle (dsDNA-RT)	HBV	Inhibition of viral replication; inhibition of infected cell proliferation; reduction in cytotoxicity in infected cells; decrease in serum DNA in mice (in vivo)	[270,271]

6.4. Toxicity of Stilbenoids

The toxicity of stilbenoids is of interest both regarding their pharmacological applications and also concerning their use as food supplements. In most studies, oral administration of resveratrol has not been associated with toxicity-related side effects or adverse effects [416]; in some cases, mild side effects have been reported [417], and the intensity of (mostly gastrointestinal) effects increases at repeated doses of over 2.5 g [416]. Single doses, even this high, do not seem to be causing any problems during testing [418,419], even though the interaction of stilbenoids with other drugs has not been researched [420].

Specifically on the stilbenoids mentioned in this paper, in their antibacterial, antifungal, antiviral, or antiparasitic capacity, from the vastness of research results mentioned, few efforts have focused on the toxicity of the compounds used.

For pterostilbene, little to no toxicity was reported [148,150].

In the case of piceatannol, toxicity remains relatively high, and this also explains its anticancer potential. For example, in the study of Duarte et al. [84], cytotoxicity against RAW macrophages was achieved at 5.7 μg/mL, while for the reference drug it was >25 μg/mL. In another study, however, against peritoneal macrophages, the toxicity limit of piceatannol and pterostilbene was found to be much higher than the active concentrations [202]. Yet other results report that there is no in vitro toxicity at effective concentrations, and very limited toxicity in test animals [211,212]. On the other hand, cytotoxicity against infected cells was high in the research of Wang et al. [273], but this was the intended effect against infected cells.

For resveratrol, even though it may have antileishmanial potential, its use in clinical practise may be hindered by its cytotoxicity against both infected and non-infected cells, in particular cell lines [206]. In another study [204], resveratrol was again found to be effective against L. braziliensis, but at a concentration also potentially toxic to healthy cells. Other experiments, where resveratrol was combined with amphotericin B, did not find any notable cytotoxicity at the concentrations against parasites [201,207]. Experiments on its antifungal potential again noted no significant toxicity against certain cell types, in the concentrations used [145,152].

In studies on its antiviral potential, resveratrol was found to be less cytotoxic than lopinavir, ritonavir, and chloroquine [322] and also to be mildly cytotoxic at the maximum concentration needed to effect maximum inhibition of viral replication in infected cells [325]. Against EV71, the CC₅₀ of resveratrol was far less than that of ribavirin and more than the corresponding IC₅₀ [330]; the same is the case for the antiviral action of resveratrol against CMV [272] and against DEV [275]. Against human rhinovirus and VZV, the maximum concentration used was not toxic [287,332].

6.5. Bioavailability of Stilbenoids

In general, compared to other more well-studied compounds, there is a relative lack of data on the pharmacokinetic properties of stilbenoids [421]; because the class is made up of different compounds, each with its own particularities, it is difficult to reach a generalized conclusion [421,422]. Like most compounds, an important regulator of bioavailability is their structure. When ingested, a part of their metabolization takes place in the liver and intestines [421,422]. At the level of the liver, either glucuronidation or sulfation takes place—the latter is believed to be associated with the cardioprotective and anticancer effect [423]. As presented in the introduction, stilbenoids have different water solubilities. Amongst the aglycones, piceatannol is the most soluble one, with pinosylvin being practically insoluble; the presence of hydroxyl groups increases the tendency of the compounds to dissolve in the aqueous phase. For drug compounds, it is generally accepted that higher water solubility values are desired [424]; more lipophilic compounds will not generally be absorbed in the GI tract and may even lead to compound precipitation and toxicity [425]. Compound stability inside the GI tract is also influenced by structure; in general, a balance between hydrophilicity and hydrophobicity is required [426]. Glycosides are generally more water-soluble, and glycosylation is generally associated with better pharmacokinetic parameters [427].

While it is a potent antioxidant and antimicrobial agent, resveratrol, being highly water-soluble compared to other stilbenoids, is rapidly destroyed in the stomach due to stomach acids [428]. Its oral bioavailability has been estimated to be less than 1% in a rat model, although in humans, it has been reported to reach as high as 75% [429]. Piceid, on the other hand, has been found to have a good GIT absorption [200], and pterostilbene appears to have better oral bioavailability than resveratrol, in rat models [430].

Analogues of resveratrol, which may even have a higher efficiency in inhibiting certain metabolic pathways, are also apparently better absorbed via the gastrointestinal tract [204]. Piceatannol is considered more metabolically stable than its precursor molecule, resveratrol, even if it may require structural modifications for its bioactivity to be enhanced in certain pathways [78]. Collectively, the systematic use of stilbenoids in medicine is hampered by their poor oral bioavailability and water solubility, their high rate of metabolic breakdown, and relatively non-specific nature in targeting cellular and tissue targets [420]. Research is underway to find alternatives that circumvent these shortcomings [431,432].

Therefore, it is apparent that some solutions on matters of bioavailability may be required; these can be provided by novel systems, which are currently under development, such as liposomes, micelles, micro-emulsions and nano-emulsions, colloidal capsules, and solid nanoparticles. All these may be viable carriers for the stilbenoids presented herein [433,434,435]. Another avenue, specifically addressing those cases where there is a risk of surgical site infections [436,437,438,439,440,441], would be the incorporation of stilbenoids in 3D-printed biomaterials [442,443,444,445,446].

6.6. Recommendations for Further Research

Given the anticancer effects of several different stilbenoids, it should be explored how they can be used, most probably as adjuvant therapies, along with more traditional radiotherapy or chemotherapy; one example would be the combination with somatostatin analogues in cases of hepatocellular carcinoma [447,448,449,450,451].

As the stilbene core is a very versatile and useful chemical structure [452]—indeed, raloxifene and tamoxifen, two stilbene-based drugs, are already commercially available [453]—further development along this axis could result in other viable pharmacotherapeutic solutions. The development of synthetic analogues, with longer half-lives and better bioavailability, will also potentially address the current limitations of biological stilbenes [454]. Regarding stilbene extraction, apart from the need for developing more environmentally friendly and efficient methods for extraction, the use of industrial and agricultural byproducts is gaining traction as another source of stilbenes [455,456,457,458]. Further research on the ethnomedical and ethnopharmacological traditions of different cultures will also potentially reveal more plant-derived stilbenoid sources and a wider spectrum of applications.

Lastly, we would like to note that there is a potential for the use of stilbenoids or their analogues in the agricultural sector to promote plant resistance to infectious agents [459]. This will help reduce the use of pesticides and fertilizers, which have a negative environmental impact [460,461,462,463]. Some stilbenoid-producing plants are also under research for their larvicide potential [464,465,466], which are also dangerous for the environment [467].

Some stilbenoid-producing plants have also been under research in attempts at phytoremediation of mining sites and water purification [468,469,470] and they can be a novel and effective solution to combat heavy metal pollution in mining and industrial sites [471,472,473,474,475,476,477,478]—in all these applications, stilbenoids probably form an integral part of the effectiveness of these plants and it should be explored how much of this activity is attributable to stilbenoids themselves.

7. Conclusions

Stilbenoid phytoalexins, comprising astringin, piceid, piceatannol, pterostilbene, pinosylvin, and resveratrol, have a host of beneficial health properties. These include antifungal, antiparasitic, and antiviral properties that are exerted via inhibition of replication of the pathogenic organisms, interference in their metabolic mechanisms, or cytoprotective effects. Of note, a few studies have been conducted in vivo in test animals, and protection against infection has been documented, especially in the cases of viruses. Further studies should focus on questions of bioavailability, which may be resolved using novel delivery techniques. Finally, future research should focus on further documenting the mechanisms of action and examining their potential against other pathogens.