INTRODUCTION:

Kostanecki and Tambor in (1899) coined the term “Chalcone”. Other names for chalcones are benzylideneacetophenone or phenyl styryl ketone. The structure of chalcone having two benzenoid rings which were joined by an aliphatic chain of 3-C (carbons). Chalcones are structurally one of most diverse group of flavonoids and effectively permit to cyclize forming flavonoid structure which is isomeric key step for the skeletal alteration of chalcone. Aromatic groups are connected to each other in the presences of α, β unsaturated ketonic system and 3-C highly electrophilic in nature having a linear structure^1,2,3. They have ketoethylenic moiety (–CO–CH=CH–) in their structure. They have a conjugated double bond and an entirely delocalized π-electron-containing order on aromatic rings. Chalcones are scrutinize as a precursor for the preparation of compounds which shows pharmacological importance⁴. Chalcone chemistry grows more interest for scientists in the 21^st century, due to their large variety of pharmacological potencies like anti-inflammatory^5-11, antioxidant^12,13, antimalarial^1,14, antimicrobial^11,15-29, antiviral³⁰, analgesic⁶, antihistaminic^31,32, antiulcer³³, antidiabetic^34-39, anticancer^{7,14,28,40-43}, antigout as xanthine oxidase inhibitors⁴⁴, antileishmanial⁴⁵ etc. (Fig. 1).

Fig. 1: Various pharmacological activities of chalcone

Increase in bile secretion by metochalcone occurs by stimulating the liver⁴⁶ and sofalcone are utilized as an antiulcer agent, which results in increasing the concentration of PG from mucosa which results in causing gastroprotection from Helicobacter pylori-persuade ulcers⁴⁷. Clinical trials showed that hesperidin trimethyl chalcone was effective for trunk or branch varicosis⁴⁸ and hesperidin methylchalcone showed effectiveness for chronic peripheral venous lymphatic insufficiency^49,50.

Majority of commonly found food chalcones are flavokavains in kava plants^51,52, chalconaringenin in tomatoes^53,54,55, phloretin^56,57,58 and its glucoside phloridzin, i.e., phloretin 2′-O- β- glucopyranoside which are present in apples, Arbutin in pears^59,60. Chalcone shows excellent moiety due to which a wide range of new heterocyclic compounds with good pharmacological potencies can be designed.

Methods of Preparation:

Chalcones consists of a simple moiety that makes its derivatization easy with simple and easy synthetic procedures. Currently, a broad range of synthetic schemes are available for the synthesis of various chalcone analogs.

Claisen-Schmidt condensation:

In the Claisen-Schmidt condensation, the concentration of alkali frequently ranges between 10 and 60%. Claisen-Schmidt condensation is most convenient method employing the diversity of catalysts such as NaOH^19,61, LiOH;H₂O⁶², K₂CO₃⁶³, KOH⁶⁴, AlCl₃⁶⁵, Ba(OH)₂, HCl⁶⁶, boric acid⁶⁷, CsOH-γAl₂O₃⁶⁸, cesium salts of 12-tungstophosphoric acid⁶⁹, H₅PMo₁₀-V₂O₄₀/SiO₂⁷⁰, SiO₂-H₃PO₄⁷¹, B₂O₃-ZrO₂⁷² and silica-H₂SO₄⁷³.

Aldol condensation reaction:

The preparatory material for this reaction is acetophenone and benzaldehyde as a Claisen-Schmidt reaction. In the very first step, acetophenone is treated with a base similar to KOH, which converts it into a more active form, its enolate form. Later it is reacted with benzaldehyde to form an intermediate which, upon heating, loses a molecule of water to form chalcone⁷⁴.

Suzuki reaction:

Chalcones can be obtained by Suzuki reaction. This reaction occurs by combining styryl boronic acid and benzoyl chloride using CsCO₃, Pd(PPh₃)₄ and anhydrous toluene or by condensing phenyl boronic acid with cinnamoyl chloride using CsCO₃, Pd(PPh₃)₄ and anhydrous toluene^75,76.

Chalcones by Suzuki coupling

Heck reaction:

Chalcones and various flavonoids can be prepared by condensation of an aryl vinyl ketone and an aryl iodide under Heck reaction conditions⁷⁷.

Synthesis of chalcone by cinnamic acid:

Chalcones have been obtained by cinnamic acid and derivatives. Cinnamic acid and phenol, cinnamic derivatives such as, cinnamoyl chloride and benzene, cinnamoyl chloride and phenol, cinnamic anhydride have been used to prepare chalcones and their analogs⁷⁸.

Synthesis of chalcone by Schiff bases:

Aryl-aminoketones derived by Schiff bases which in the presence of acid will undergo hydramine cleavage and produces primary aromatic amine and chalcones as products⁷⁹.

Solvent-free synthesis:

That reactions between solids occurred because of the formation of a liquid melt⁸⁰. This indicated the existence of liquid phase—which could be a eutectic mixture formed upon mixing the reactants or one of the reactants itself—is a prerequisite for reaction to occur. The high concentration of reactants in these solvent-free but liquid environments is would be responsible for observed acceleration of reaction rates. Upon mixing the benzaldehyde and the acetophenone, the mixture melted even before adding the NaOH. With grinding of the solid NaOH, the liquid mixtures became pasty as the solid product of chalcone was formed in the separated solution. Siddiqui in 2015 reported a convenient green approach for the HClO₄–SiO₂ catalyzed synthesis of coumarinyl chalcones under solvent-free conditions⁸¹.

One-pot synthesis:

One-pot synthesis of chalcones was recently performed using CuI/carbon sphere (CSP) nanocomposites and anomalous selectivity under the green conditions CuI/CSP nanocomposites were synthesized by refluxing the mixture of CuI and CSP in ethanol. The CSP were prepared by hydrothermal carbonization of glucose at 180^OC. The CuI was then stabilized on the polysaccharide surface of CSP by mixing CuI and CSP in an equal ratio in ethanol under conventional reflux conditions. E-selective heterocyclic chalcones with 75–93% yield was obtained as major products in the presence of 3-methylpiperidine, piperidine, pyrrolidine and piperazine⁸².

Chalcone synthesis using ultrasound irradiation:

Heterogeneous catalysts such as potassium carbonate, basic Al₂O₃, amino-grafted zeolite, Ba(OH)₂, pulverized KOH and KF-Al₂O₃ were used with effectiveness for the preparation of chalcones and their analogs under ultrasound irradiation⁸³. Ultrasound-assisted synthesis has been another dominant procedure like microwave irradiation-assisted synthesis because of the fact that it finishes the reaction with short duration of time and produces a high percentage of products. For preparation of chalcones and derivatives under ultrasound irradiation, heterogenous catalysts like, KF-Al₂O_3, K₂CO₃, basic Al₂O_3, pulverized potassium hydroxide (KOH), NaOH, are used productively^38,84-88.

Sonogashira Isomerization Coupling:

In this Sonogashira coupling–isomerization reaction, the chalcones are prepared by treating equimolar amounts of electron-deficient (hetero) aryl halides and (hetero) aryl or alkenyl 1-propargyl alcohols in THF, catalyzed by PdCl₂(PPh₃)₂ under microwave radiation⁸⁹.

Sonogashira coupling–isomerization reaction for chalcone synthesis

Anti-Inflammatory Activity:

Won and co-workers prepared (E)-1-(2-hydroxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one, which is a chalcone derivative and confirmed bioactivity in vitro for its inhibitory effect on chemical mediators produced from mast cells, macrophages, neutrophils and microglial cells, with good results. 20-hydroxy-3,4-dichlorochalcone, which possesses anti-inflammatory and cancer chemopreventive activity, was synthesized by⁹⁰, Dihydro xanthohumol, which is isolated from the fruit of Mallotus philippensis by Zhao and co-workers⁹¹ exhibited anti-inflammatory activity. A reduced chalcone having cyclooxygenase-2 inhibitory activity was isolated by⁹².

Bano and coworkers synthesized a new chalcone series i.e., 2-hydroxy chalcone, 2-methoxy chalcone, flavanones and flavones which were evaluated for having anti-inflammatory potency by carrageenan induced rat paw edema model using indomethacin as standard drug⁹³.

Ozdemir and associates synthesized a series of novel indole-based chalcones from 5-substituted-1H-indole-3-carboxaldehydes or 1-methylindole-3-carboxaldehyde that is appropriate acetophenone derivatives. The derivatives were screened for in-vivo inhibitory activities against COX-1 and COX-2 out of which two compounds were found to show anti-inflammatory activity⁹⁴.

Bandgar and coworkers synthesized various nitrogen containing chalcone derivatives by Mannich reaction and were screened for anti-inflammatory activities⁹⁵.

Jadhav and associates reported the synthesis of numerous fluoro-hydroxy substituted pyrazole chalcones by using polyethylene glycol as an alternative reaction medium. The synthesized derivatives were evaluated for in vitro anti-inflammatory activities by an assessment of their ability to inhibit the expression of COX-1 and COX-2. Indomethacin was applied as a reference drug⁹⁶.

Nyandoro and coworkers synthesized 2-hydroxy-3,4,6-trimethoxy chalcone from the root and stem bark extracts of Toussaintia orientalis. At a dose of 30 μg/mL, the isolated chalcone derivative showed 50% inhibition of COX-1 having IC₅₀ value of 95.5 μM. Moreover, it also caused substantial inhibition (88%) of COX-2 at 30 μg/mL⁹⁷.

Yadav and coworkers synthesized a novel series of chalcone analogues by Claisen–Schmidt condensation of acetophenone with various substituted benzaldehyde in the presence of a base. The synthesized compounds were screened for anti-inflammatory activities using the carrageenan-induced rat hind paw edema model in mice. The anti-inflammatory effect of these compounds is associated with the inhibition of COX and reduced prostaglandin formation⁹⁸.

Jantan and coworkers synthesized various 4-methlyamino ethanol substituted and methoxylated chalcone derivatives which were evaluated for having anti-inflammatory activity taking Indomethacin as standard drug⁹⁹.

Bandgar and coworkers synthesized novel chalcone derivatives and screened them for their possible inhibitory effects against COX, Lipopolysaccharide (LPS)-stimulated TNF-α and pro-inflammatory enzymes such as trypsin and β-glucuronidase⁹⁵.

Bukhari and associates synthesized chalcone derivatives using ethyl 2-(4-carboxyphenylazo) acetoacetate and various benzaldehydes and were reported to show potent anti-inflammatory activities against COX-1 and COX-2¹⁰⁰.

Zhang and coworkers synthesized a new series of hydroxy chalcones and dihydroxy chalcones and were tested for having potent anti-inflammatory activity¹⁰¹.

Hasan and coworkers synthesized fluorinated chalcone by Claisen– Schmidt condensation using SOCl₂/EtOH, which was evaluated to possesses potent anti-inflammatory property¹⁰².

Dhar and coworkers isolated 2′,4-dihydroxy-3′,4′,6′-trimethoxychalcone from Chromolaena odorata (L.) and was investigated to show anti-inflammatory potency against the lipopolysaccharide-induced inflammation in RAW 264.7 macrophages. Results showed that the compound causes significant decrease in the production of NO and cytokines, TNF-α, pro-inflammatory interleukin-1β and IL-6⁵.

Antioxidant Activity:

Different chalcones were synthesized by grinding process between various aromatic ketones and aromatic aldehydes in the presence of solid NaOH and their antioxidant activity was assessed in vitro using the DPPH free radical scavenging assay¹⁰³.

A rational sequence of chalcones, including oleoyl chalcones, monohydroxy chalcones, Schiff base derived chalcones, copper and zinc metal complexes, were synthesized and tested as strong antioxidant agents¹⁰⁴.

Claisen-Schmidt condensation of various substituted acetophenone and benzaldehydes yielded a new series of chalcones derivatives, which were screened for antioxidant activity using four assays: hydrogen peroxide scavenging assay, reducing power assay, DPPH radical scavenging assay, and superoxide radical scavenging assay¹⁰⁵.

Substituted chalcones derivatives

Miranda and co-workers synthesized a prenylated and nonprenylated chalcones and flavanones that were tested to exhibited antioxidant activity¹⁰⁶.

Claisen–Schmidt condensation of 2-acetyl-5-chlorothiophene and various benzaldehyde derivatives in the presence of NaOH as catalyst and methanol as solvent at room temperature produced a variety of novel chalcone derivatives with heterocyclic moieties, which were investigated for antioxidant activity¹⁰⁷.

The antioxidant activity of a novel series of fatty acid chalcone esters was evaluated after esterification of various chalcone derivatives with some fatty acids for which chalcone precursors were synthesized by Claisen-Schmidt condensation between various acetophenones and some substituted benzaldehydes in the presence of NaOH¹⁰⁸.

Various hydroxyl chalcones were prepared by condensation between corresponding acetophenone and benzaldehydes in the presence of acid and base which were investigated to possess antioxidant potency for scavenging activity towards galvinoxyl radical (GO^.)¹⁰⁹.

The condensation of dihydroxy acetophenone and different benzaldehydes, followed by reaction with DMSO in the presence of iodine, yielded a new series of 2,4-dihydroxy chalcones, which were investigated for antioxidant activity¹¹⁰.

CONCLUSION:

From the literature, it can be stated that chalcones and their derivatives shows a wide spectrum of biological activities, viz anticancer, antioxidant, anti-inflammatory activities, antimicrobial, anticonvulsant etc. That is why the attention of scientists has increased towards chalcones in searching for novel and biologically potent derivatives from them. This review focuses on anti-inflammatory and antioxidant activity of various chalcone derivatives from the literature.

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Received on 09.04.2021 Modified on 20.08.2021

Asian J. Pharm. Res. 2022; 12(1):37-44.

DOI: 10.52711/2231-5691.2022.00007