Chalcones: A review on synthesis and pharmacological activities

of this article was presented at CUDC consortium and Summer School Conference at Chitkara University. ____________ Goyal et al. / Journal of Applied Pharmaceutical Science 11 (Supp 1); 2021: 001-014 002 Chalcones have been known from earlier times to have an interesting moiety which is associated with a wide range of pharmacological activities. The majority of commonly found food chalcones are phloretin (Gerhauser, 2008; Mariadoss et al., 2019; Min et al., 2015) and its glucoside phloridzin, i.e., phloretin 2′-0βglucopyranoside which are present in apples, chalconaringenin in tomatoes (Echeverria et al., 2009; Kolot et al., 2019; Slimestad and Verheul, 2011), Arbutin in pears (Reiland and Slavin, 2015; Sasaki et al., 2014), and flavokavains in kava plants (Liu et al., 2018; Pinner et al., 2016). Chalcone possess a very good moiety due to which a variety of novel heterocyclic compounds with better pharmacological properties can be designed. Structure of a chalcone METHODS OF SYNTHESIS OF CHALCONES Chalcones possess a simple moiety which makes its substitutions easy with simple and easy methods of synthesis. Currently, a wide range of schemes are available to synthesize various chalcone analogs. Claisen–Schmidt’s condensation It is a commonly employed and easy method (Scheme 1). In the method, chalcones are synthesize by condensing substituted or unsubstituted benzaldehyde with substituted or unsubstituted acetophenone with the use of bases or acids as catalysts in an appropriate solvent at about 50°C–100°C for few hours (Kaur and Narasimhan, 2018; Khanapure et al., 2018; Monga et al., 2014; Özdemir et al., 2017; Rahman et al., 2007; Reddy and Kathale, 2018). It is normally carried out in the liquid phase, but some syntheses occur in the solid phase, like resin was bound with acetophenone compounds and then reacted with benzaldehyde compounds (Mahapatra et al., 2015) or under solvent-free conditions such as catalytic condensation in the presence of triazabicyclodecene (Fringuelli et al., 2004). Additionally, microwave-assisted liquid and solvent-free condensation decrease synthesis time and elevate the production yield (Kakati and Sarma, 2011; Srivastava, 2008). Carbonylative Heck’s coupling reaction Chalcones have been synthesized by vinylation of aryl halide (such as phenyl halide) with styrene under carbon monoxide and the catalyst palladium can undergo carbonylative coupling (Bianco et al., 2003; Wu et al., 2010) (Scheme 2). Suzuki–Miyaura’s coupling reaction This coupling reaction takes place by combining benzoyl chloride and styryl boronic acid using Pd(PPh3)4, CsCO3, and anhydrous toluene or by combining phenyl boronic acid and cinnamoyl chloride using Pd(PPh3)4, CsCO3, and anhydrous toluene (Selepe and Van Heerden, 2013) (Scheme 3). Sonogashira’s isomerization coupling This reaction involves the synthesis of chalcones by the microwave coupling of the electron-insufficient group, like phenyl halide, and prop-2-yn-1-ol and catalyst PdCl2(PPh3)2 and solvent like tetrahydrofuran (THF) (Braun et al., 2006; Takahashi et al., 1980) (Scheme 4). Continuous-flow deuteration reaction Ynones basically were synthesized by the process available in the literature by the reaction of benzoyl chloride and phenylacetylene under Sonogashira’s conditions and then for deuteration, which was carried out in an H-Cube system caused by replacing H2O with D2O as the deuterated source (Hsieh et al., 2015; Ötvös et al., 2016) (Scheme 5). Solid acid catalyst-mediated reaction Chalcones are prepared by using a solid acid catalyst which is heterogeneous in nature (Scheme 6). It involves the addition of aromatic aldehyde (such as benzaldehyde) and ethynyl benzene in ethylene dichloride solvent using a microwave condition and using ion-exchange resin, like amberlyst-15, as the solid acid catalyst (Rueping et al., 2011)

Chalcones have been known from earlier times to have an interesting moiety which is associated with a wide range of pharmacological activities. The majority of commonly found food chalcones are phloretin (Gerhauser, 2008;Mariadoss et al., 2019;Min et al., 2015) and its glucoside phloridzin, i.e., phloretin 2′-0β-glucopyranoside which are present in apples, chalconaringenin in tomatoes (Echeverria et al., 2009;Kolot et al., 2019;Slimestad and Verheul, 2011), Arbutin in pears (Reiland and Slavin, 2015;Sasaki et al., 2014), and flavokavains in kava plants (Liu et al., 2018;Pinner et al., 2016). Chalcone possess a very good moiety due to which a variety of novel heterocyclic compounds with better pharmacological properties can be designed.

METHODS OF SYNTHESIS OF CHALCONES
Chalcones possess a simple moiety which makes its substitutions easy with simple and easy methods of synthesis. Currently, a wide range of schemes are available to synthesize various chalcone analogs.

Claisen-Schmidt's condensation
It is a commonly employed and easy method (Scheme 1). In the method, chalcones are synthesize by condensing substituted or unsubstituted benzaldehyde with substituted or unsubstituted acetophenone with the use of bases or acids as catalysts in an appropriate solvent at about 50°C-100°C for few hours (Kaur and Narasimhan, 2018;Khanapure et al., 2018;Monga et al., 2014;Özdemir et al., 2017;Rahman et al., 2007;Reddy and Kathale, 2018). It is normally carried out in the liquid phase, but some syntheses occur in the solid phase, like resin was bound with acetophenone compounds and then reacted with benzaldehyde compounds (Mahapatra et al., 2015) or under solvent-free conditions such as catalytic condensation in the presence of triazabicyclodecene (Fringuelli et al., 2004). Additionally, microwave-assisted liquid and solvent-free condensation decrease synthesis time and elevate the production yield (Kakati and Sarma, 2011;Srivastava, 2008).

Carbonylative Heck's coupling reaction
Chalcones have been synthesized by vinylation of aryl halide (such as phenyl halide) with styrene under carbon monoxide and the catalyst palladium can undergo carbonylative coupling (Bianco et al., 2003;Wu et al., 2010) (Scheme 2).

Continuous-flow deuteration reaction
Ynones basically were synthesized by the process available in the literature by the reaction of benzoyl chloride and phenylacetylene under Sonogashira's conditions and then for deuteration, which was carried out in an H-Cube system caused by replacing H 2 O with D 2 O as the deuterated source (Hsieh et al., 2015;Ötvös et al., 2016) (Scheme 5).

Solid acid catalyst-mediated reaction
Chalcones are prepared by using a solid acid catalyst which is heterogeneous in nature (Scheme 6). It involves the addition of aromatic aldehyde (such as benzaldehyde) and ethynyl benzene in ethylene dichloride solvent using a microwave condition and using ion-exchange resin, like amberlyst-15, as the solid acid catalyst (Rueping et al., 2011)

One-pot synthesis
It is an easy, efficient, and green method that allows the chalcone synthesis in a single reactor (Scheme 8). The reaction mixture consists of phenyl methanol and acetophenone with an oxidizing agent such as CrO 3 . CrO 3 generates the benzaldehyde from phenyl methanol, which then involves the reaction with the acetophenone to give chalcone (Mahapatra et al., 2015).

Synthesis of chalcones using Schiff bases
Schiff bases result in aryl amino ketones, which in the presence of an acid lead to hydramine breakdown and produce products such as primary aromatic amine and chalcones (Abe et al., 2003;Gaonkar and Vignesh, 2017).

Ultrasound irradiation-assisted synthesis of chalcone
Ultrasound-assisted synthesis is another advantageous technique like microwave irradiation-assisted synthesis due to the fact that it completes the reaction within short period of time and yields a high percentage of products. For the synthesis of chalcones and their derivatives under ultrasound irradiation, heterogenous catalysts like K 2 CO 3 , pulverized potassium hydroxide (KOH), NaOH, basic Al 2 O 3 , KF-Al 2 O 3 are used productively (Adole et al., 2020;Calvino et al., 2006;Cancio et al., 2019;Li et al., 2002;Polo et al., 2019;Rammohan et al., 2020).

PHARMACOLOGICAL ACTIVITIES
Various chalcones and their derivatives have been synthesized and reported to have pharmacological activities like antimicrobial, antimalarial, anticancer, antifungal, anthelmintic, antiinflammatory, anti-HIV, monoamine oxidase inhibition, antiangiogenic, antileishmanial activities, etc. A brief outline of some of the selected pharmacological activities is presented in the following sections.

Chalcone as an antimicrobial agent
α, β-unsaturated keto functions as highly reactive species, which shows nucleophilic conjugate addition of important protein due to which it shows antimicrobial activity.
The synthesis of a new chalcone series with benzimidazolyl group was carried out to produce antimicrobial agents by condensing N-(4-(1Hbenzo[d]imidazol-2-yl)phenyl) acetamide with benzaldehyde-related compounds using aqueous KOH at room temperature (Baviskar et al., 2009).
Novel nitrochalcones were synthesized to produce antimicrobial agents by condensing nitroacetophenone with some aromatic aldehydes by using a base at room temperature (Monga et al., 2014).
Chalcones AA (1-6) were prepared by Claisen-Schmidt's condensation of 2-acetyl pyridine and aldehyde derivatives in diluted ethanolic KOH at room temperature (Prasad et al., 2008). Physical properties of chalcones are presented in Table 1. Chalcones AB are synthesized by condensing aldehydes with o-hydroxyl acetophenone, followed by reaction with I 2 and dimethyl sulfoxide (DMSO), which results in the synthesis of flavones and which shows antimicrobial property (Rathore et al., 2015).

R = H, OH, Cl, NO 2
Some of the novel fluorinated chalcones, AC, AD, AE (1-13), have been synthesized and tested for antitubercular activity for Mycobacterium tuberculosis H37Rv and antimicrobial activity for fungi and pathogenic bacteria (Burmaoglu et al., 2017).
A novel series of dehydroacetic acid chalcone-1,2,3triazole analogs AH (1-16) was designed and synthesized. The synthesized compounds were evaluated for antimicrobial activities against four bacterial and two fungal strains (Lal et al., 2018).

Chalcones as anticancer agents
The synthesis of a novel sequence of 2′,5′-dialkoxyl chalcones BA (1-10) was carried out by condensing various aromatic ketones with various suitable and substituted benzaldehydes. The compounds were evaluated to show antitumor and chemopreventive activities (Cheng et al., 2008). A new quinazolinone-chalcone derivative was prepared by condensing the substituted aromatic aldehyde and substituted aromatic ketone in Ba(OH) 2 and testing it for possessing anticancer activity (Wani et al., 2015).
A novel series of chalcones BB (1-12) with 3-aryl thiophene-2-aryl and hetero aryl moieties was prepared and tested to show in vitro anticancer property for human colon cancer cell lines (Venkataramireddy et al., 2016). Novel derivatives of chalcones BD were prepared by condensing appropriate acetophenones and various benzaldehydes, followed by the reaction of the produced product (chalcone) with sodium acetate in ethanol to give flavanones BE, which were evaluated as antiproliferative agents (Ketabforoosh et al., 2014).
Fluorinated chalcone analog was prepared by Claisen-Schmidt's condensation and by reacting with SOCl 2 /EtOH, which possesses a powerful anti-inflammatory property (Hasan et al., 2012).
Novel chalcones containing the isopropyl group (iPr), viz. compounds CA and CB, were prepared by Claisen-Schmidt's condensation and were evaluated as active anti-inflammatory agents (Chen et al., 2013).
A novel dihydroxy chloro chalcone was prepared and tested to be a potent anti-inflammatory agent (Zhang et al., 2010).
In a recent study, a new series of chalcone analogs containing Apocynin and 5-Nitrofuran group have been reported. Compounds CD-CN were prepared by Claisen-Schmidt's condensation, which was carried out under solvent-free conditions and was evaluated as active anti-inflammatory agents (Reddy and Kathale, 2018).

Chalcones as antioxidants
A sequence of novel derivatives of chalcones DA (1-6) with heterocyclic moiety was prepared by Claisen-Schmidt's condensation of 2-acetyl-5-chlorothiophene and various benzaldehyde derivatives with a catalytic amount of NaOH and methanol as solvents at room temperature and evaluated as antioxidant agents . A new series of 2,4-dihydroxy chalcones DB (1-5) was prepared by the condensation of dihydroxy acetophenone and various benzaldehydes, followed by reaction with DMSO in the presence of iodine to give flavonoids DC (1-5), which were evaluated for antioxidant activity (Murti et al., 2013). A new series of derivatives of chalcones was synthesized and tested for antioxidant activity (Wu et al., 2014).

Chalcones as an antiepileptic
A new series of chalcones was prepared through Claisen-Schmidt's condensation, which was further tested for antiepileptic property (Sharma et al., 2013).
A new chalcone series EA (1-10) was synthesized which incorporated hydrazide derivatives and were evaluated as anticonvulsant agents (Kumar and Chauhan, 2015).

Chalcones as antidiabetic agents
A novel series of chalcone-based aryl oxypropanolamine FA, FB, FC, and FD was synthesized and evaluated as powerful antidiabetic and antidyslipidemic agents (Shukla et al., 2017).
A new series of 60 derivatives of chalcone were synthesized having substitutions on Ring A or were unsubstituted by Claisen-Schmidt's condensation of some aromatic ketones with various benzaldehydes in 50% w/v KOH/H 2 O with solvent ethanol. Out of these 60 derivatives, 12 derivatives were found to be active as antidiabetic agents (Hsieh et al., 2012). R 1 = H, OH, F, Cl, Br, I; R 2 = H, OMe, OBn, -OCH 2 O-A series of chalcone FE and its 2-pyrazoline analogs FF, FG, FH, FI, and FJ was prepared and tested to be antidiabetic agents (Emayavaramban et al., 2013).

Chalcones as antihypertensive agents
Novel chalcones GA (1-7) were synthesized, consisting of pyrimidine as the basic moiety, and tested to be potent antihypertensive agents (Bukhari et al., 2013). Studies were carried out on vasorelaxant and antihypertensive properties of dihydrospinochalcone and Isocordoin isolated from Lonchocarpus xuul (Avila-Villarreal et al., 2013).

Compound
Novel chalcones with quinoline in their structure GB were prepared and tested to have powerful antihypertensive moiety .

Chalcones as antimalarial agents
Three aminoalkylated derivatives of chalcones HA (1-3) were synthesized by Claisen-Schmidt's condensation between chloroacetophenone and vanillin. After this reaction, addition of the amine group was carried out through Mannich's reaction. The synthesized derivatives were evaluated for antimalarial activity against Plasmodium falciparum strain (3D7) and molecular docking was also performed. Molecular docking and biological evaluation shows that compound HA2 was the most active derivative among the synthesized derivatives (Syahri et al., 2020).

CONCLUSION
From this review, it can be stated that chalcones and their derivatives show a wide spectrum of biological activities, viz anticancer, antimicrobial, anticonvulsant, antioxidant, antiinflammatory activities, etc. That is why the attention of scientists has increased towards chalcones in searching for novel and biologically potent derivatives from them.