INTRODUCTION:

Chalcones chemistry has created comprehensive scientific investigations all through the world. Particularly interest has been centered around the synthesis and biodynamic potencies of chalcones. The name "Chalcones" was given by Kostanecki and Tambor¹.

Chalcones are scrutinized as precursor of isoflavonoids and flavonoids which are one of the significant classes of natural products like vegetables soya, fruits, flavors and tea. The natural chalcones and its synthetic analogs display a wide range of pharmacological potencies^2-4. Chalcone has become an essential lead atom for its significant pharmacological activities, including antimicrobial^5-15, antioxidant¹⁶, antibacterial¹⁷, antileishmanial¹⁸, anticancer^19,20, antidiabetic²¹and anti-inflammatory²² activities. Licochalcone, a naturally occuring flavonoid with chalcone moiety, exhibited potent antimycobacterial action against several strains of mycobacterium and demonstrated that halogenated chalcones as potent antitubercular agents²³. Their activities are structure dependent and the chemical nature of flavonoids relying upon their structural class, degree of hydroxylation, different replacements and formations and degree of polymerization²⁴. Naturally, chalcone is a yellowish pigment with significant properties in the organic synthesis and therapeutic field²⁵. 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 chalcones. Accordingly, from pharmacological investigations, various unadulterated chalcones isolated from various plants have been rectified for clinical trials for treating malignancy, viral and cardiovascular problems or have been incorporated in cosmetic preparations²⁶. The chemistry of chalcones is still an attraction among the organic chemist from earlier times, because of open-chain model and the element of skeletal modification to produce a new class of organic compounds such as azachalcones²⁷, isoxazoles²⁸, pyrazoles^5,29and indole grounded chalcones³⁰. In chalcones, two aromatic rings and the electrophilic α, β-unsaturated carbonyl system are in conjugation in continous manner. It could be the reason of their low redox potential, stability, electron transfer reactions and more significantly for its promising biological activities^31,32. Chalcones are readily synthesized in the laboratory by different synthetic methods like Claisen-Schimdt condensation^5,32,33, aldol condensation^34,35, Suzukireaction³⁶, Heck reaction³⁷, Sonogashira isomerization coupling^38,39, Microwave-assisted synthesis of chalcones⁴⁰, Preparation of chalcones utilizing cinnamic acid⁴¹,Preparation of chalcones from organometallic compounds⁴² etc. Structural alterations of chalcones format can be promptly accomplished. The most convenient technique is the Claisen-Schimdt condensation between equimolar amounts of arylmethylketone with arylaldehyde in the presence of alcoholic alkali⁵.

Methods of preparation

Claisen-Schimdt condensation

The Claisen–Schmidt condensation is the most broadly applied method in organic chemistry due to simple procedure and greater yields as in comparison to other conventional methods. This synthesis has a simple procedure for the synthesis of chalcone derivatives, in which acetophenone and aromatic aldehyde undergo condensation in the presence of acid or base catalysts in polar solvents at 50–100°C for several hours^32,33. It has been reported that a series of fluoro-substituted chalcones with greater yields (80–90%) by employing Claisen-Schmidt condensation of trimethoxy acetophenone with various fluoro-substituted aldehydes in aqueous solution of base⁴³. In another attempt, preparation of a novel prenylated chalcones was carried out by Claisen–Schmidt condensation in LiOH/MeOH with moderate yields⁴⁴.In general, Claisen–Schmidt condensation reaction is carried out in both liquid phase as well as in solid phase^45,46. In solid-phase reaction, acetophenone derivative was initially bounded to the resin and then reacted with various derivatives of benzaldehydes. Although Claisen–Schmidt condensation is successfully carried out by using base for the preparation of chalcones, Lewis acids and Bronsted acids are also have been utilized as catalysts. The acid-catalyzed Claisen–Schmidt condensation was carried out using HCl in ethanol, but the yields were very poor (10–40%)⁴⁷. The most well-known and frequently selected route to synthesize chalcone is Claisen-Schmidt condensation, which involves condensation of ketone and aldehydes, with minimal work-up and less side products^48,49.

Aldol condensation reaction:

The preliminary material for this reaction is acetophenone and benzaldehyde as a Claisen-Schmidt reaction. In the absolute initial step, acetophenone is treated with a base like KOH, which converts it into a more active structure, its enolate structure. Later it is reacted with benzaldehyde to form an intermediate which, upon heating, loses a molecule of water to form chalcone^34,35.

Suzuki reaction:

Chalcones can be prepared by Suzuki reaction. In general, the scheme consists of a reaction between benzoyl chloride and phenyl vinyl boronic acid (high yield) or among phenyl boronic acid and cinnamyl chloride (moderate yield)³⁶.

Heck reaction

Chalcones and other flavonoids can be prepared by coupling an aryl vinyl ketone with an aryl iodide under Heck reaction conditions³⁷.

Preparation of chalcones using cinnamic acid:

Chalcones have been obtained using cinnamic acid and its derivatives⁴¹. Cinnamic acid and phenol, cinnamic derivatives such as cinnamic anhydride, cinnamoyl chloride and benzene, cinnamoyl chloride and phenol have been used to prepare chalcones and their analogs⁵⁰.

Preparation of chalcones from organometallic compound:

Literature have reported the synthesis of chalcones using organometallic compounds such as cadmium derivatives, acetylenic Grignard reagents and cinnamyl chloride in ether, cinnamonitrileand phenyl magnesium bromide in the presence of methylmagnesium iodide and ammonium chloride with benzaldehyde⁴².

Sonogashira isomerization coupling:

Sonogashira coupling can be defined as when terminal alkynes are coupled with aryl halides in the presence of catalyst palladium which is combined with a co-catalytic amount of Cuprous iodide in a boiling mixture of THF and trimethylamine, under inert conditions for 16–24 h^38,39. In this condition, various chalcones were prepared with moderate to high yields. But, Sonogashira coupling has limitations like extended reaction times, need for electron-deficient aryl halides and required quite excess base. To minimize these limitations, a microwave-assisted isomerization coupling reaction for the preparation of chalcones within half-hour reaction period in usefullyields⁵¹.

Microwave-assisted synthesis of chalcones:

Mistry and Desai used a microwave technique to synthesize chalcones⁵². Heterogeneous catalysts including potassium carbonate, barium hydroxide, p-Toluenesulfonic acid, KF-Al₂O₃⁵³.Zirconium tetrachloride, piperidine and aqueous alkali have been used for the preparation of chalcones and analogs using microwave irradiation⁴⁰.

Pharmacological Activity of chalcones:

Fig. 1: Various pharmacological activities of chalcones

Several chalcones and derivatives have been prepared and reported to possess various pharmacological properties like anthelmintic, antileishmanial, anti-inflammatory, antimalarial, anti-HIV, antimicrobial, antioxidant, monoamine oxidase inhibition, antifungal, antiangiogenic, anticancer activities etc. (Fig. 1). In the following sections, antimicrobial activity and antioxidant properties of chalcones have been discussed.

Chalcones as antimicrobial agents:

α, β-unsaturated carbonyl system acts as hugely reactive moieties showing nucleophilic conjugate addition of predominant proteins because of which it displays antimicrobial activity.

Various novel nitrochalcones were prepared by reacting nitroacetophenone with various aromatic aldehydes using base at room temperature and were evaluated to possess antimicrobial activity against 4 different strains of bacteria and 3 strains of fungi⁵.

New series of chalcone having benzimidazolyl group was accomplished by condensation between N-(4-(1H-benzo[d]imidazol-2-yl) phenyl) acetamide and benzaldehyde-related derivatives utilizing aqueous KOH at room temperature which were screened for antimicrobial activity⁵⁴.

Various chalcones were synthesized by Claisen–Schmidt’s condensation between 2-acetyl pyridine and several benzaldehydes in the presence of dilute ethanolic KOH at room temperature⁵⁵.

2-acetyl pyridine

Novel chalcones were prepared by condensation between aldehydes with o-hydroxyl acetophenone, further by reacting with dimethyl sulfoxide (DMSO) and I₂ results in the formation of flavones which shows antimicrobial potency⁵⁶.

Several novel fluorinated chalcones have been prepared and were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv and antimicrobial activity for pathogenic bacteria and fungi⁴³.

Recently, coupling of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrolidine-2,5-dione, 1-(2,6-dichloro-4-trifluoromethyl-phenyl) piperidine-2,6-dione and several aromatic aldehydes in the presence of acetic acid yields chalcones which were shown to possess antimicrobial potency⁵⁷.

Compound	Main Structure
1
2
3
4
5

Novel chalcone series were synthesized by Claisen–Schmidt’s condensation of 2-acetyl-1-methylpyrrole and 5-(aryl)-furfural analogs which then were tested to show antimicrobial activities against 5 pathogenic bacteria and 4 fungi⁵⁸.

Compound	R	Compound	R
6		11
7		12
8		13
9		14
10		15

A series of dehydroacetic acid chalcone-1, 2, 3-triazole analogs were designed and prepared and were evaluated to show antimicrobial activities against 4 bacterial and 2 fungal strains⁵⁹.

Compound	R	Compound	R
1	C₆H₅-	9	3-BrC₆H₄CH₂-
2	2-CH₃C₆H₄CH₂-	10	4-BrC₆H₄CH₂-
3	3-CH₃C₆H₄CH₂-	11	2-FC₆H₄CH₂-
4	4-CH₃C₆H₄CH₂-	12	3-FC₆H₄CH₂-
5	2-N0₂C₆H₄CH₂-	13	4-FC₆H₄CH₂-
6	3-NO₂C₆H₄CH₂-	14	4-OCH₃C₆H₄-
7	4-NO₂C₆H₄CH₂-	15	4-BrC₆H₄-
8	2-BrC₆H₄CH₂-	16	4-NO₂C₆H₄-

A simple chalcone was prepared by Claisen-Schmidt condensation between 4-methoxybenzaldehyde and acetophenone in the presence of aqueous KOH and was evaluated for its antimicrobial and antifungal activities taking Ciprofloxacin and Amphotericin-B as standard drug respectively⁶⁰.

A novel series of fused pyridine and pyrimidine derivatives were synthesized via chalcone synthesis as intermediates and were tested for their antibacterial and antifungal activity against various pathogenic strains⁶¹.

Claisen-Schmidt aldolic condensation of 2-hydroxy-3, 4, 6-trimethoxy acetophenone and various substituted benzaldehydes in the presence of ethanolic NaOH yielded a new series of chalcones that were tested for antibacterial efficacy against various pathogenic bacterial strains⁶².

Antioxidant Activity:

A series of new chalcone derivatives having heterocyclic moieties was synthesized by Claisen–Schmidt condensation between 2-acetyl-5-chlorothiophene and several benzaldehyde derivatives in the presence of NaOH as catalyst and methanol as solvent at room temperature and were evaluated for antioxidant activity⁶³.

Compound	R₁	R₂	R₃	Compound	R₁	R₂	R₃
1	I	H	H	4	OCH₃	H	H
2	H	I	H	5	H	OCH₃	H
3	H	H	I	6	H	H	OCH₃

A new series of 2, 4-dihydroxy chalcones was prepared by the condensation of dihydroxy acetophenone and various benzaldehydes, followed by reaction with DMSO in the presence of iodine to give flavonoids which were evaluated for antioxidant activity⁶⁴.

Compound	R₁	R₂	R₃	R₄
1	H	OH	H	H
2	H	OMe	H	H
3	H	Cl	H	H
4	H	H	NO₂	H
5	OMe	OH	H	OMe

Miranda and co-workers synthesized a prenylated and nonprenylated chalcones and flavanones that were tested to exhibited antioxidant activity⁶⁵.

A novel series of fatty acid chalcone esters have been synthesized by 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 NaOH and were evaluated for exhibiting antioxidant activity⁶⁶.

A rational series of various chalcones were prepared which includes oleoyl chalcones, monohydroxy chalcones, Schiff base derived chalcones and copper and zinc metal complexes which were evaluated as potent antioxidant agents⁶⁷.

A new series of chalcones derivatives were synthesized by Claisen-Schmidt condensation between various substituted acetophenone and benzaldehydes which were screened for antioxidant activity by means of four assay such as hydrogen peroxide scavenging assay, reducing power assay, DPPH radical scavenging assay and superoxide radical scavenging assay⁶⁸.

Substituted chalcones derivatives

Various hydroxyl chalcones were prepared by condensation between corresponding acetophenone and benzaldehydes in the presence of acid and base which were evaluated to possess antioxidant potency for scavenging activity towards galvinoxyl radical (GO^.)⁶⁹.

Different chalcones were synthesized by condensation reaction between various aromatic ketones and various aromatic aldehydes in the presence of solid NaOH by grinding method and were evaluated to possess antioxidant activity in vitro activity by DPPH free radical scavenging method⁷⁰.

CONCLUSION:

From the literature, it can be stated that chalcones and their derivatives shows a wide spectrum of biological activities, viz anticancer, antimicrobial, anticonvulsant, antioxidant, anti-inflammatory activities, 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 antimicrobial and antioxidant activity of various chalcone derivatives from the literature.

CONFLICT OF INTEREST:

None.

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Received on 13.04.2021 Modified on 24.11.2021

Asian J. Res. Pharm. Sci. 2022; 12(1):21-28.

DOI: 10.52711/2231-5659.2022.00005