Chalcones (natural or synthetic derivatives) are aromatic ketones possessing a central backbone that form a core for variety important compounds with different substitutions. Recent scientific advances show that chalcones exhibit different bio-medical activities, including antiviral, which is related to the variety substitutions. This review provides general information on the origin, sources, virucidal and direct antiviral properties of chalcones in vitro, as well as a brief overview of the possible application and molecular modes of action of these compounds. The antiviral effect of chalcones probably results from the disruption of the different stage of viral replication cycle, inhibition of viral or cell enzymes, induction of apoptosis and others. Structural requirements for antiviral activities vary according to the mechanisms of action. Based on the published information, it could be considered that synthetic chalcones are very perspective antiviral candidates and deserve further studies for elucidating of their pharmacological potential.

antiviral effect, chalcones, in vitro, synthetic derivatives

Medicinal plants represent the main source of bioactive compounds and secondary metabolites, such as phenolic, nitrogen and sulfur compounds, carotenoids, terpenoids, alkaloids, anthocyanins and other (Manach et al. 2004; Bucar et al. 2013; Harvey et al. 2015; Fierascu et al. 2020). Phytochemicals possess great structural diversity, for instant the majority of them are heterocyclic, although some are aliphatic (noncyclic) with different substituents in the main backbone chain (Newman and Cragg 2007; Lafay and Izquierdo 2008). These substances have attracted the attention of scientist centuries because for their diverse bio-pharmacological activities and medicinal properties (Hartmann 2007; Savoia 2012; Wink 2012; Pusztahelyi et al. 2015; Fridlender et al. 2015; Kapoor et al. 2017; Bulliyya 2017). Recently, it is clearly known that they play a crucial role for preventing against different types of diseases and promoting human health (Hamburger and Hostettmann 1991; Pretorius 2003; Dai and Mumper 2010).

In traditional medicine, large number of candidate substances such as phytochemicals and their synthetic derivatives were found to be useful in the treatment and prevention of some diseases with viral origin (Abad et al. 2000; Novakova et al. 2018; Dhama et al. 2018; Akram et al. 2018). Alarmingly, the number of patients, regardless of gender, age and geographical location, diagnosed with viral infections is increasing dramatically every year. Some of these viruses that attack humans and animals are very aggressive with high infective potential such as Ebola, influenza, SARS (severe acute respiratory syndrome), COVID-19 (severe acute respiratory syndrome coronavirus 2), AIDS (acquired immunodeficiency syndrome) and other (Feldmann et al. 2003, 2012; Benvenuto et al. 2020).

Viruses are obligate intracellular parasites, which contain either RNA or DNA, and some of them could be surround by a lipid‐containing envelope. Consequently, viruses have adapted to all life organisms and conditions resulting in different diseases ranging from self-limiting to pandemics (Wagner and Hewlett 1999). Viruses have numerous invasion strategies and for their replication use the normal cellular metabolic pathways. This strategy makes it difficult to find a specific treatment and to attack the virion directly, or some steps of its replication, without to make adverse effects on the host-cells (Wagner and Hewlett 1999). Moreover, the major difficulty in developing of specific and targeted therapy is due to viral variations (He et al. 2009; Haagmans et al. 2009). Ninety antiviral drugs available today treat some viruses, included HIV (human immunodeficiency virus), HBV (hepatitis B virus), HCV (hepatitis C virus), HSV (herpes simplex virus), VZV (varicella zoster virus), influenza virus and HCMV (human cytomegalovirus) (Gilks et al. 2006; Wilson et al. 2009; Ahmed 2011; Vigano et al. 2012). Currently, there is no approved specific therapy in preventing or treating the majority of viral infection, as well as safety and efficacy vaccine against all types of viruses (Hewson 2000; Rollinger and Schmidtke 2011; Small and Ertl 2011; Liu et al. 2015). However, systemic application of antivirals often possesses limited efficacy, serious side effects and led to development of resistance (Piret and Boivin 2011; Kristen et al. 2016; Aves et al. 2018). Based on that, phytochemicals and their synthetic derivatives are very promising and may be a proper alternative for treating and preventing these medical problems (Abad et al. 2000; Naithani et al. 2008; Novakova et al. 2018). At present, it is necessary to highlighting the possibility and challenges of applied strategies for the delivery of these biologically active substances to the right target in the host-cells and to overcoming the multiple biological barriers (Ben-Shabat et al. 2020; Watkins et al. 2015). A wide variety of active antiviral phytochemicals and their derivatives have been isolated, purified and investigated recently, including chalcones, which belongs to the flavonoids family (Dhar 1981; Gaonkar and Vignesh 2017). They are also intermediates in the synthesis of flavones (Chavan et al. 2016).

The term “chalcones” have given from Stanisław Kostanecki and Josef Tamboror, who first perfomed the pilot synthesis of these coloring compounds in laboratory conditions (Rayees Ahmed et al. 2011). Naturally, chalcones are abundant in fruits, vegetables, tea, spices, ferns, and are often responsible for the yellow pigmentation in some plant species such as Glycyrrhiza, Angelica, Coreopsis, Asteraceae, Ruscus, Piper, which have been used in Asia, Africa and South America as medicine from the centuries (Rayees et al. 2011; Singh et al. 2014; Chavan et al. 2016). Pure chalcones have been an area of great interest and extensively studied for their pharmaceutical properties in recent years. Several chalcone-based substances were approved as a therapeutics in clinical practice. One of them is metochalcone ((1-(2,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-2-propen-1-one), which use as a choleretic drug, the others sofalcone, (2- [5- [(3-methyl-2-buten-1-yl) oxy] -2- [3- [4- [(3-methyl-2-buten-1-yl)oxy] phenyl] -1-oxo-2-propen-1-yl] phenoxy] acetic acid) was previously used as an antiulcer and mucoprotective drug (Opletalova et al. 2000; Batovska and Todorova 2010). Clinical trials have shown that these compounds are not toxic, reached reasonable plasma concentration and are well tolerated.

Structurally, chalcones are aromatic compounds (1,3-diphenyl-2-propene-1-one), in which two aromatic rings (ring A and B), forms the central core and are linked by a three carbon α,β-unsaturated keton system (Rayees Ahmed et al. 2011; Zhou and Xing 2015). The most of the natural chalcones are polyhydroxylated in the aryl rings (Dimmock et al. 1999; Zhuang et al. 2017). Since the chalcone back bone is found to be very potent as intermediate for the preparation of substances with clinical potentials against various diseases. This has lead to the need for synthesizing chalcone derivatives, which possess different useful pharmacological activities, such as antimicrobial, antiviral, antifungal, anti-oxidant, antitumor, anti-inflammatory, antiulcerative, antiparasitic, antimalarial, immunomodulatory, antihyperglycemic, antiproliferative and others (Haraguchi et al. 2002; Wang et al. 2004; Go et al. 2005, Kumar et al. 2013; Matos et al. 2015; Karthikeyan et al. 2015; Caamal-Fuentes et al. 2015, Funakoshi et al. 2015). Chalcones are synthesized by two reactions: Claisen-Schmidt condensation and base-catalyzed aldol condensation between appropriately substituted aldehydes and ketones or acid catalyzed followed by dehydration (Claisen and Claparede 1881; Palaniandavar and Natarajan 1980; Morrison and Boyd 2004; Singh et al. 2014). The chalcones are characterized by an extensive structural diversity (Zhuang et al. 2017). The synthetically derived chalcones may also contain one or more aryl substituents, which contain halogens, alkyl, amino, nitro, acetamido and carboxyl groups (Singh et al.2014; Zhuang et al. 2017). Actually, many chalcons and their synthetic analogs demonstrate broad spectrum of biological activities, which are highly appreciated in many areas of today’s life such as medicine for the treatment of cancer, cardiovascular diseases, viral and parasitic infections, food industry as a food additives, in agriculture as a plant growth regulator and to control weeds and unwanted pests (Duke et al. 2000; Kang et al. 2004; Ni et al. 2004; Lee et al. 2004; Shen Jeu et al. 2005). Some chalcone derivatives have also abilities to inhibit several important enzymes in cells, such as xanthine oxidase, aldose reductase, epoxide hydrolase, protein tyrosine kinase and quinone reductase (Sogawa et al. 1994; Iwata et al. 1999; Miranda et al. 2000; Yang et al. 2001; Nerya et al. 2004). However, much of the pharmacological potential of chalcones is still not utilized and not clearly understood. For that reason, they are of great interest amongst the scientists.

The purpose of this mini review is to provide an overview especially of the in vitro and in vivo antiviral activities of naturally occurring and synthetic chalcones and to highlights their efficacy against some viruses, potential mechanism of action and relevant structure-activity relationships.

Pure chalcones and their synthetic analogs have not been intensively studied for their potency as antivirals inhibitors. Therefore further research on their biosynthesis, mechanisms of the antiviral therapeutic effect and the development of successful target-drug delivery systems are of interest of many research groups worldwide. According to the published scientific literature, the antiviral properties of a number of chalcones have been studied on some plant and human viruses. However, experimental data show that the various antiviral activities of the studied chalcones depend on their specific substitution patterns (Table 1). Antiviral effect of chalcones against some plant viruses

Table 1.

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Antiviral effect of chalcones and their derivatives against some plant and human viruses.

№	Chalcone derivatives		Antiviral activity	Reference
1				Dimmock et al. 1999
	Basic structure of chalcones
2			Inactivation effect against tobacco mosaic virus (TMV) coat protein (CP)	Dong et al. 2017
	5-((3,3-dichloroallyl)oxy)-2-(3-(3-(4-(4-methoxyphenyl)hex-1-en-2-yl)phenoxy)propoxy)-1,3-dimethylbenzene
				Tang et al. 2019
	(E)-1-(2-(2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)ethoxy)phenyl)-3-(4-fluorophenyl)prop-2-en-1-one
				Guo et al. 2019
	1. R = Ph; 2. R = 2-FPh; 3. R = 2-Br-Ph; 4. R = 2-NO2-Ph; 5. R = 3-CH3-Ph; 6. 3,4-di-OCH3-Ph
3			Inactivation effect against TMV and cucumber mosaic virus (CMV)	Zhou et al. 2018
	(E)-2-methyl-N-(4-(3-(4-((9-methyl-9H-purin-6-yl)oxy)phenyl)acryloyl)phenyl)benzenesulfonamide
4		Complexes of Cu(II), Ni(II) and Zn(II) with the following ligands:	Inactivation effect against tobacco ringspot virus (TRSV)	Mallikarjun 2005
		1. R = H, R1 = H (PHPO)
		2. R = Cl, R1 = H (CPHPO)
		3. R = OCH3, R1 = H (MPHPO)
		4. R = OCH3, R1 = OCH3 (DMPHPO)
5		2‘,3‘,4‘,4-tetrahydroxychalcone	Inactivation effect against tomato ringspot virus (ToRSV)	Onyilagha et al. 1997
6		(Z)-2,4-dihydroxy-3-(3-hydroxy-3-phenylacryloyl)-6-methoxy-5-methylbenzaldehyde	Inhibition of human immunodeficiency virus (HIV) replication	Wu et al. 2003
6		(E)-1-(3,4-dihydroxy-5-methoxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one	Inhibition of human immunodeficiency virus (HIV) replication	Uchiumi 2003
		(E)-3-(4-hydroxy-2-methoxy5-(2-methylbut-3-en-2-yl)phenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one
		(E)-3-(3,4-dihydroxy-2-methoxyphenyl)-1-(4-hydroxyphenyl)prop-2-en-1-one
7		3-(4-hydroxyphenyl)-1-(2,4,6-rihydroxyphenyl) propan-1-one, Phloretin	Inhibition of HIV-1 protease activity	Xu et al. 2000
		(E)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one, Butein
		(E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3-phenylprop-2-en-1-one, Cardamonin		Cheenpracha et al. 2006
8		(E)-1-(2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, Xanthohumol	Inhibition of HIV-1 reverse transcriptase and p24 antigen	Wang et al. 2004
9			Inhibition of human influenza A virus replication and neuraminidase	Bizzarii et al. 2019
	stilben derivatives
		1. R1 = H, R2 = NO2, R3 = H		Pradip et al. 2016
		2. R1 = H, R2 = H, R3 = OCH3
10			Inhibition of herpes simplex virus (HSV) replication	Stompor et al. 2019
	1-(2,6-dihydroxy-4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)-3-(4-hydroxyphenyl)propan-1-one
11			– Anti-rubella virus effect	– Ahmad et al. 2008
			– Anti – human poliovirus effect	– Ishltsuka et al. 1982
	(E)-1-(4-ethoxy-2-hydroxy-6-methoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one		– Anti-rhinovirus effect	– Ninomiya Y. et al. (1984)
12		1-(3,5-dichloro-2-hydroxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one	Antiviral effect against hepatitis C virus (HCV)	Mateeva et al. 2017
		3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-5-methyl-3-nitrophenyl)prop-2-en-1-one
13		1. R = C6H5	Antiviral effect against hepatitis A virus (HAV)	Gouhar et al. 2018
		2. R = 4-NH2C6H4
	4-(Naphthalen-2-yl)-2-oxo-6-(5-((3-(trifluoromethyl)phenyl)diazenyl)benzofuran-3-yl)-1,2-dihydropyridine-3-carbonitrile
14		(E)-1-(2,4-dihydroxy-6-methoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, Helichrysetin	Inhibition of Middle East respiratory syndrome-related coronavirus (MERS-CoV) protease	Jo et al. 2019
	(E)- 1- (2,4-dihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, Isobavachalcone
15			Inhibition of severe acute respiratory syndrome-related coronavirus (SARS-CoV) protease	Park et al. 2016
	(E)-1-(3-(2-hydroperoxy-3-methylbut-3-en-1-yl)-2-hydroxy-4-methoxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one, Xanthoangelol E

Several numbers of studies have been done on the anti-infective effects of synthetic chalcones derivatives against the tobacco mosaic virus (TMV). This virus infects a wide range of plants, especially tobacco, vegetable and other members of the Solanaceae family and causes uncontrolled crop loss Bos (2000). Dong et al. 2017 have synthesized a series of novel chalcone derivatives containing the 1,1-dichloropropene moiety and studied them for anti-infective activity against TMV. The experimental data showed that the most of the tested chalcone derivatives exhibited moderate to good inactivation effect against TMV at 500 μg/mL except one that achieved a stronger effect in vivo at EC₅₀ of 45.6 μg/mL (effective concentration 50%). The latter was similar to that of the common antiviral drug ningnanmycin (46.9 μg/mL) but higher as compared to that of ribavirin (145.1 μg/mL). In addition, fluorescence spectroscopy and the microscale thermophoresis (MST) showed that one of the tested compound strongly interacted with the TMV coat protein, but the mechanism of inactivation was not clear (Dong et al. 2017).

In addition, series of novel chalcone derivatives containing 1,2,4-triazine moiety were synthesized by Tang et al. (2009) for activity against TMV infection. Antiviral assays revealed that most of them possessed a curative, protective and inactivation potential against the virus at a concentration of 500 μg/mL^-1in vivo. The obtained results demonstrated notably that 1,2,4-triazine scaffold showed a better anti-TMV activity than that of ningnanmycin. Only one compound of the set had a significant protective effect with EC₅₀ = 79.4 mg/mL^-1 and dissociation constant (Kd) value of 0.275 ± 0.160 μmol/L^-1 to the TMV coat protein (TMV-CP). Molecular docking studies with TMV-CP showed that the compound was embedded well in the pocket between the two subunits of TMV-CP.

Other promising chalcone derivatives, containing a thiophene sulfonate group were synthesized and their antiviral efficacy against TMV was evaluated in vivo (Guo et al. 2019). Six compounds among them showed excellent curative activities against TMB. Microscale thermophoresis (MST) techniques for the biophysical analysis of interactions between biomolecules showed that the binding capacity of two of the chalcone derivatives to TMV-CP were better than that of the commercial ningnanmycin. It can be indicated from these results that some thiophene sulfonate chalcone derivatives could be further investigated in the area of the pesticide science as potential antiviral agents.

Аt about the same time, Zhou et al. (2018) studied the biological activity and the selectivity of novel chalcone derivatives containing a purine and benzenesulfonamide moiety against TMV and cucumber mosaic virus (CMV) in vivo. The obtained data indicated that several of the derivatives revealed significant anti-TMV and anti-CMV effect, which corresponded with a lower EC₅₀ value (51.65 μg/mL) as compared to the antiviral agent ribavirin (150.45 μg/mL). In particular, one of the tested chalcone derivatives revealed a prominent inactivation activity against both viruses.

Other interesting research on plant viruses demonstrated that complexes of Cu(II), Ni(II) and Zn(II) with of 3-(phenyl)-1-(2’-hydroxynaphthyl)–2–propen–1–one (PHPO), 3-(4-chlorophenyl)-1-(2’-hydroxynaphthyl)–2–propen–1–one (CPHPO), 3-(4-methoxyphenyl)-1-(2’-hydroxynapthyl)-2-propen-1-one (MPHPO) and 3-(3,4-dimethoxyphenyl)–1-(2`-hydroxynaphthyl)–2-propen–1–one (DMPHPO) inhibited the tobacco ring spot virus (TRSV) growth on cowpea (Vigna sinensis) leaves indicating that they were more toxic to the virus than the respective ligands (Mallikarjun 2005). This effect can be ascribed to the property of the metal ions to interfere with normal cellular processes. It is evident from the mechanisms mentioned above that the toxic activity of a complex depend on the stability of the complex in solution. Complexes with higher stability and greater lipid solubility are more toxic towards the virus and inhibit more effectively the virus growth.

Other examples for naturally occurring chalcones that can protect the crop as eco-friendly pesticides and weed control agents has been reported from Malhotra et al. (1996). For the first time, they found out that a 2-hydroxychalcone slightly inhibits the tomato ringspot virus (ToRSV) replication in Chenopodium quinoa. A hydroxy and methoxy substituted chalcone derivatives were investigated by Onyilagha et al. (1997) against ToRSV infection. This study demonstrated that the antiviral activity was activated by hydroxylation of the A-ring at 2‘,3‘,4‘ positions and B-ring at C-4‘, suppressed by hydroxylation at C-5‘, and reduced by methoxylation of the B-ring.

In summary, chalcones are naturally coloring compounds with an unsaturated side chain found in various edible plant species, precursors of flavonoids and isoflavonoids. During the last decades, it was proven that the chalcone backbone is very effective, with an array of biological activities. This has given rise to the need for discovery and synthesis of new synthetical chalcones with different constituents as pharmaceutically important molecules. Synthetic and naturally occurring chalcones have been reported to possess various medical properties, including direct anti-viral and virucidal activities. A few numbers of studies were focused on the anti-infective activity of chalcones against plant and human viruses. This review provides information on the anti-viral effect of chalcones (whether natural and synthetic derivatives) in vitro, as well as an overview of the mechanisms of actions and possible medical applications of these compounds. In general, chalcones are versatile molecules with a broad range of biological activities, including anti-viral, and a wide variety of application areas. However, more investigations are needed to fully understand the molecular targets and mechanisms, in which they are involved.