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 International Journal of Medical Sciences and Pharma Research 

Open Access to Medical Science and Pharma Research

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An Updated Review on Recent Advancements in the Diverse Biological Applications of Medicinally Privileged Scaffold: Chalcone and its derivatives

Praveen Sekar, Shridharshini Kumar, Senthil Kumar Raju*

Department of Pharmaceutical Chemistry, Swamy Vivekanandha College of Pharmacy, Tiruchengode – 637 205, Tamilnadu, India

Introduction

The term "heterocyclic compound" refers to organic molecules that have at least one carbon atom with at least one other heteroatom, such as an N, O or S atom. For the metabolism of biological cells, they are essential. They often have five or six members and some of their rings have compositions that are greater than those of rings with three, four, seven or more members. Heterocyclic chemistry has drawn significant interest in the pharmaceutical and synthetic organic chemistry because of the wide range of pharmacological and therapeutic implications¹. One of the most significant groups of heterocyclic molecules with extensive medicinal applications is chalcones, which can be produced synthetically or naturally as flavonoids. Chemically speaking, the chalcone is composed of polyphenolic molecules from the flavonoid family called 1,3-diphenyl-2-propene-1-one. The chalcones are open-chained molecules with two aromatic rings that are connected by three carbon chains that each include a carbonyl group and an α,β-unsaturated bond^2-4. Moreover, these substances can be found in naturally occurring products like plant allelochemicals and insect hormones. Chalcones undergo a wide range of chemical reactions in addition to being used to make heterocyclic compounds. It is possible to create a wide range of chalcone derivatives by combining aromatic aldehydes with aryl ketones by utilizing the proper amount of condensing agents. Chalcones serve as the initial intermediate structure in the synthesis of flavonoids, isoflavonoids and aurones in many biosynthetic pathways⁵.  Chalcone has two aromatic rings with p-electron systems and conjugated double bonds with absolute delocalization, giving them a relatively low redox potential and a higher likelihood of undergoing electron transfer processes⁶.

Similar to chalcones, coumarins, hydroxy coumarins, chalconoids and curcuminoids are naturally occurring moieties with an, -unsaturated carbonyl system, extending their potential towards cancer. For example, the compounds containing hydrazide-hydrazone, acrylonitrile, and 2-amino-3-cyanopyridine moieties displayed significant anticancer potential⁷. The chalcones and their derivatives were made using a variety of synthetic techniques, such as base-catalysed condensation reaction⁸, Claisen-Schmidt condensation⁹, Knoevenagel condensation¹⁰, microwave- and ultrasonic-assisted synthesis^11,12, refluxing¹³, stirring at high temperature¹⁴ and molecular hybridization¹⁵. The Claisen-Schmidt condensation method was by far the most effective in synthesizing chalcones and their derivatives. 

These chalcones and their derivatives have been reported to exhibit a wide variety of therapeutic and pharmacological applications including anticancer¹⁶, antimicrobial¹⁷, antitubercular¹⁸, antioxidant¹⁹, anti-inflammatory²⁰, larvicidal²¹, antiplasmodial²², neuroprotective²³, cholinesterase inhibitors²⁴, antidepressant²⁵, anti-diabetic²⁶ and vitiligo treatment²⁷. Among these therapeutic uses, chalcones and their derivatives have focused more on cancer since they can control tumor neo-angiogenesis and have improved anticancer potential by blocking many signaling pathways while having low toxicity to normal cells^28,29.

In this review, only the literature indexed in Scopus, PubMed, Google Scholar, Embase, ResearchGate and Web of Science databases were collected by using the keywords such as chalcones, diphenyl propene-1-ones, Claisen-Schmidt condensation, antimicrobial, anticancer, antioxidant, anti-inflammatory, antitubercular and therapeutic applications, individually and in combination between the time period of 2016 to 2023. Here, we summarized the various biological applications of novel and efficient chalcones and their derivatives.

Antimicrobial activity of chalcones and their derivatives

Antibiotic-resistant organisms have a negative impact on the effectiveness of antibiotics, despite the fact that they are considered one of the most effective therapies in medicine. (E)-3-(3,4-dimethoxyphenyl)-1-(2-hydroxy-4-((1-(2-(4-methoxyphenyl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)prop-2-en-1-one (1) was synthesized by irradiation of propargylated chalcone with 4-methoxy phenacyl azide under microwave conditions. The compound was evaluated for its antimicrobial activity and was found to be active against Staphylococcus aureus, determined by the inhibition of biofilm formation¹⁷. (E)-1-(3′-aminophenyl)-3-(4-bromophenyl)prop-2-en-1-one (2) was synthesized and evaluated its antimicrobial efficacy, found to be highly active against S. aureus³⁰. Azulene‐containing chalcone, (E)-1,3-Di(azulen-1-yl)prop-2-en-1-one (3) was prepared by the reaction between 1-azulenecarbaldehyde and ketone in ethanol. The antimicrobial efficacy of the synthesized compound was evaluated and found to be active against the fungal strain, Candida parapsilosis³¹. Novel (E)-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1-ones (4,5) were synthesized and evaluated its potential against Aspergillus spp. using broth microdilution method. Both of these compounds were found to be highly active and possessed fungicidal activity³². (2E)‑1,3‑diphenyl prop‑2‑en‑1‑one (6) and (2E)‑3‑[4‑(dimethylamino)phenyl] ‑1‑phenyl‑ prop‑2‑en‑1‑one (7) were synthesized by the reaction of 1‑(2,2‑Dimethylchroman‑6‑yl)ethanone with substituted benzaldehydes under stirring conditions. The antifungal activity of the synthesized compounds was tested against Botrytis cinerea and Monilinia fructicola using an in vitro radical growth rate assay. Compound (6) was active against B. cinerea and compound (7) was found to be active against M. fructicola. Similarly, the compound (8), (2E)‑3‑(benzo[d] [1,3]dioxol‑5‑yl)‑1‑(2,2‑dimethyl‑ chroman‑6‑yl)prop‑2‑en‑ 1‑one, the dihydrochromane–chalcone hybrid was also found to be a potent antifungal agent. I.e., effective against M. fructicola³³. 

Based on the Claisen-Schmidt condensation, the two novel chalcones namely, (2E)-1-(4′ -aminophenyl)-3-(phenyl)‑prop-2-en-1-one (9), and (2E)-1-(4′-aminophenyl)-3-(4-chlorophenyl)‑prop-2-en-1-one (10) was designed and prepared by the condensation of p-aminoacetophenone and benzaldehyde with ethanol. The designed compounds were subjected to evaluate the antibacterial efficacy against different microorganisms and found to be highly effective against S. aureus. Compound (9) exhibited synergistic activity with the standard compound, gentamycin, while compound (10) was non-synergistic with it. The reason for the loss of synergistic activity was due to the presence of the halogen substituents³⁴. Fluorinated chalcone-1,2,3-triazole conjugates were designed and synthesized by Yadav et al., 2018. The antimicrobial potential of the designed compounds was tested against both gram-positive (S. epidermidis and Bacillus subtilis), gram-negative (Escherichia coli and Pseudomonas aeruginosa) microorganisms and antifungal (A. niger and C. albicans) microorganisms. Among the designed compounds, the compound, (E)-1-(4-bromophenyl)-3-(2-((1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)prop-2-en-1-one (11) was found be active against the fungal strain, C. albicans. The compound, (E)-3-(2-((4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-methoxy phenyl)prop-2-en-1-one (12) was found to be active against both A. niger and C. albicans. On focussing towards antibacterial, the compound, (E)-3-(2-((1-(4-fluorobenzyl-1H-1,2,3-triazol-4-yl)methoxy)naphthalene-1-yl)-1-(4-nitro phenyl)prop-2-en-1-one (13) was highly effective against P. aeruginosa³⁵. 

Fluoro-substituted chalcones were synthesized and evaluated their efficiency as antimicrobial agents. The compound (2E)-3-phenyl-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (14) and (2E)-3-(2-fluorophenyl)-1-(2,4,6-trimethoxyphenyl)prop-2-en-1-one (15) was found to be effective against the tested fungal strains, C. albicans, C. glabrata, and C. parapsilosis and the compound (14) also exhibited better bactericidal activity against S. aureus, S. pyogenes, Enterococcus faecalis, E. coli and P. aeruginosa bacterial strains³⁶. The thiazole-based chalcones were designed, synthesized and the antibacterial potential was evaluated by Alrohily et al., 2019. Among the various derivatives, the compound (E)-9-)(4-methoxybenzylidene)-5-(4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-thiaolo[2,3-b]quinazoline (16) was found to be highly effective against both gram-positive and gram-negative bacterial species, S. aureus and Micrococcus luteus, determined by the antibiofilm activity³⁷.

Figure 1: Compounds possessing antimicrobial activity

Antitubercular activity of chalcones and their derivatives

Chalcone-sulphonamide hybrids (17,18) were synthesized by the reaction between various sulphonamide derivatives and aromatic aldehydes by the Claisen-Schmidt condensation reaction. The obtained chalcone hybrids were tested against the Mycobacterium tuberculosis H37Rv strain to determine the antitubercular efficiency of the compounds. The compounds (E)-N’-Isonicotinoyl-2,4-dimethoxy-5-(3-(3,4,5-trimethoxyphenyl)acryloyl) benzenesulfonohydrazide (17) and (E)-5-(3-(Benzo[d][1,3]dioxol-5-yl)acryloyl)-N’-isonicotinoyl-2,4-dimethoxybenzenesulfonohydrazide (18) were found to be highly effective antitubercular compounds¹⁸. Pyrazole–coumarin and pyrazole–quinoline chalcones were synthesized by the reaction of pyrazole carbaldehyde and 3-acetyl coumarin/ substituted 1‐ (2‐methyl‐ 4‐phenylquinolin‐3‐yl)ethanone in the presence of piperidine, respectively and evaluated their potency as antitubercular agents against M. tuberculosis H37Rv strain using the MABA (microplate Alamar Blue assay) method. The synthesized coumarin derivative, 7‐Methoxy‐3‐[(2E)‐3‐[3‐( 4‐methylphenyl)‐1‐phenyl‐1H‐pyrazol‐4‐ yl]‐prop‐2‐enoyl] ‐2H‐chromen‐2‐one (19) and quinoline derivative, (2E)‐3‐[3‐(4‐Bromophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]‐1‐[6‐chloro‐4‐ (2‐fluorophenyl)‐2‐methylquinolin‐3‐yl]prop‐2‐en‐1‐one (20) was found to be potent compounds against the tested organism with better MIC values. The in silico molecular docking studies also revealed and confirmed that these compounds were highly active against the tubercular species³⁸. 

 Uracil-ferrocenyl chalcone conjugates (21,22) were synthesized by the reaction of O-propargylated ferrocenyl chalcone with N-alkylated-azido-uracil under continuous stirring for 10-11 h and evaluated their potential against M. tuberculosis mc²6230 strain. Both of the compounds were active against the tested strain but were found to be a loss of activity than their non-chalcone hybrids³⁹. Chalcone based on nitro thiophene analogue, (2E)-1-[4-(1H-imidazol-1-yl)phenyl]-3-(5-nitrothiofen-2-yl)prop-2-en-1-one (23) was evaluated against M. tuberculosis H37Rv strain to determine its antitubercular potential using the MABA (Microplate Alamar Blue Assay) method and found to be a potent compound for tuberculosis, which was due to the presence of nitro thiophene moiety in its structure. i.e., it showed 5.5-fold increase in the activity⁴⁰. 

The chalcone linked 5-phenyl-3-isoxazole carboxylic acid methyl ester derivative, Methyl-(E)-5-(3-(4-(3-oxo-3-(4-propoxyphenyl)prop-1-en-1-yl)benzamido)phenyl)isoxazole-3-carboxylate (24) was obtained by the condensation of Methyl 5-(3-aminophenyl)isoxazole-3-carboxylate with carbonic acid derivative. The antitubercular potential of the compound was evaluated against drug-resistant M. tuberculosis and found to be highly potent against M. tuberculosis H37Rv strain with better MIC value⁴¹.

Figure 2: Compound possessing antimicrobial (14-16) and antitubercular (17-24) activities

Antimalarial activity of chalcones and their derivatives

4-aminoquinoline-chalcone/ferrocenyl-chalcone conjugates (25,26) were prepared and reported by Singh et al., 2017. The aldol condensed product of o-bromoalkyl acetophenone with 7-chloro-4-piperazine-quinoline and substituted aryl aldehyde/ ferrocene-carboxaldehyde resulted in the formation of corresponding 4-aminoquinoline-chalcone/ ferrocenyl-chalcone hybrids was obtained, respectively. These compounds were found to be effective against chloroquine-resistant and mefloquine-sensitive W2 strain of Plasmodium falciparum with better IC₅₀ values²². The antimalarial potential of the quinolinyl chalcone (27) was evaluated against chloroquine (CQ) sensitive and resistance (CQ- resistance) strain of P. falciparum and found to be a potent compound, which was due to the presence of bromine substituent. The molecular docking studies also revealed that this compound was found to be having a better binding affinity with significant activity⁴².

(E)-3-(3,4-dihydroxyphenyl)-1-(2-hydroxy-4- methoxyphenyl) prop-2-en-1-one (28) was synthesized by the Claisen-Schmidt condensation of substituted benzaldehyde with substituted acetophenone. The antimalarial potency of the compound was evaluated against chloroquine-sensitive P. falciparum 3D7 strain and possessed excellent activity with a better IC₅₀ value. The molecular docking studies also revealed that the compound was highly active against the dihydrofolate reductases–thymidylate synthase (PfDHFR-TS) protein⁴³. Aminoalkylated chalcone derivative, (E)-1-(4-chlorophenyl)-3-(4-hydroxy-3-methoxy-5-(piperidin-1- ylmethyl)phenyl)-prop-2-en-1-one (29) was obtained by the reaction of chalcone afforded from vanillin and chloroacetophenone with formaldehyde and piperidine under stirring conditions. The resulted chalcone-based mannich base derivative (29) was found to be active against chloroquine-sensitive P. falciparum 3D7 strain, determined by both in vitro and in silico molecular docking experiments⁴⁴.

Indolyl-chalcone hybrid, Trans-3-(1H-indol-3- yl)-1-(2’-hydroxyphenyl)-2-propen-1-one (30) was also exhibited against P. falciparum, NF54 strain. The better activity of this compound was due to the presence of the hydroxyl substituent at the second position of the phenyl group, which exhibited better IC₅₀ value⁴⁵. (E)-1-(4-Chlorophenyl)-3-[3-methoxy-4-(prop-2-yn-1-yloxy)phenyl]prop-2-en-1-one was treated with propargyl bromide, afforded (E)-1-(4-Chlorophenyl)-3-(4-((1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl)methoxy)-3- methoxyphenyl)prop-2-en-1-one (31). The obtained compound was tested and found to be effective against chloroquine-sensitive P. falciparum 3D7 (Pf3D7) strain and chloroquine-resistant P. falciparum K1 strain, determined by using SYBR-Green-I assay⁴⁶. The antimalarial activity of the compound (2E)-3-(3,4-dimethoxyphenyl)-1-(3,4,5-trimethoxycyclohexa-1,3-diene-1-yl)prop-2-en-1-one (32) was evaluated using WHO Mark III schizont maturation inhibition assay and found to be active against chloroquine-resistant P. falciparum strain⁴⁷. 

Anticancer activity of chalcones and their derivatives

A novel chalcone-polyamine conjugate, Synthesis of 4-[N1 -spermidine-3-aminopropyloxy]-3',4',5' – trimethoxychalcone (33) was obtained by coupling the bromide group of 4-bromopropyloxy-3',4',5' – trimethoxy chalcone with primary amine function of polyamine by means of nucleophilic substitution reaction. The antiproliferative activity of the compound was tested against human colorectal (HT-29 and HCT116) and prostate (PC3 and DU145) cancer cell lines using an MTT assay. The tested compound was found to be highly effective against the tested cell lines and found to be blocking the G1 and G2 phase cell cycle, thus induced apoptosis³. (E)-4-chloro-N-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl) prop-1-en-1-yl) phenyl) butanamide (34) was synthesized and evaluated against MGC-803 (gastric), HCT116 (colon) and MCF-7 (breast) cancer cell lines using an MTT assay. 

Figure 3: Compounds possessing antimalarial (25-32) and anticancer (33-34) activities

The tested compound was found to be active against the tested cell lines and also found to be inducing apoptosis, determined by the western blot analysis and flow cytometry⁴. The benzo[d]imidazo[2,1-b]thiazole-chalcone conjugates (35,36) exhibited better anticancer effects against the breast cancer cell line, MDA-MB-231 with better IC₅₀ values. It was found to be inducing apoptosis, determined by annexin V-FITC/PI assay and the flow cytometry revealed that this compound arrested the cell cycle at the G2/M phase¹⁶.

The breast cancer activity of the synthesized derivative, (8S,9S,10R,13S,14S,17S)-17-[(2E)-3-(4-fluorophenyl)prop-2-enoyl]-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydro cyclopenta[a]phenanthren-3-one (37) was determined by the MTT assay. The compound was found to be active against two breast cancer cell lines namely, MCF-7 and MDA-MB-231 with better IC₅₀ values²⁸. Chalcone containing naphthalene moiety namely, (E)-3-(4-(Diethylamino)phenyl)-1-(4-methoxy naphthalen-1-yl)prop-2-en-1-one (38) was screened against HCT116 (colorectal) and HepG2 (liver) cancer cell lines and found to be highly effective against both of the cell lines. Furthermore, the tested compound induced cell cycle arresting at the G2/M phase and the molecular docking results revealed that this compound exhibited significant binding interaction with the colchicine site of tubulin⁴⁸. The other derivative of the same class, (E)-3-(3-Hydroxy-4-methoxyphenyl)-1-(2-methoxynaphthalen-1-yl)prop-2-en-1-one (39) was also found to be possessing significant anticancer activity against MCF-7 breast cancer cell line, followed by cell cycles arresting at G2/M phase⁴⁹. Similarly, the chalcone containing indole and naphthalene moieties (40) was also found to be novel tubulin polymerization inhibitors and active against liver, colon and breast cancer cells⁵⁰.

Chalcone containing thieno[2,3-d]pyrimidin-2-yl derivative, (E)-2-(3-(2,4,6-Trimethoxyphenyl)-3-oxoprop-1-en-1-yl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (41) was active against colon cancer cell line and induced apoptosis through the mitochondrial cell death pathway and induced PARP-1, caspase cleavages⁵¹. The cytotoxic potential of 6'-benzyloxy-4-bromo-2'-hydroxychalcone (42) was evaluated against a panel of cancer cell lines and found to be effective against U937, HL-60, NALM-6, MOLT-3 leukaemia cell lines. This compound induced apoptosis by generating reactive oxygen species through the mitochondrial pathway⁵². The in vitro antiproliferative activity of the compound, (E)-1-(4-Amino-2-(pyrrolidin-1-yl)thiazol-5-yl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (43) was evaluated and found to be effective against MCF-7 (breast), HepG2 (liver) and SW480 (colorectal) cancer cell lines. It also induced apoptosis by inducing the G2 phase cell cycle arresting⁵³.

(E)-1–(1-Hydroxy-4,5,8-trimethoxynaphthalen-2-yl)-3-(quinolin-6-yl) prop-2-en-1-one (44) was synthesized and found to be effective against gastric cancer cell lines (HGC27, MKN28, AZ521, AGS, and MKN1). This compound was also found to be an apoptosis-inducing agent, thus suppressed STAT3 phosphorylation⁵⁴. Novel halogenated phenoxy chalcone, 3–(4-(4-Bromophenoxy)phenyl)-1-(p-tolyl)prop-2-en-1-one (45) was evaluated and found to be active against MCF-7 breast cancer cell line using an MTT assay. It also suppressed mitogen-activated protein kinase, followed by inducing apoptosis through the blockade of the G2/M phase cell cycle⁵⁵. 3-(4-Methoxyphenyl)-1-(5-methyl-2-(methylamino)thiazol-4-yl)prop-2-en-1-one (46) was found to be exhibit broad antitumor activity and induced apoptosis by inhibiting G2/M phase cell cycle⁵⁶. The antiproliferative compound, 3-Aminomethyl pyridine chalcone derivative (47) with apoptosis-inducing capability exhibited better activity against various cancer cell lines⁵⁷. 

Figure 4: Compounds possessing anticancer activity

The xanthine oxidase inhibitory and antiproliferative activity of the derivatives, (2E,2'E)-1,1'-(2-hydroxy-4,6-dimethoxy-1,3-phenylene)bis(3-(2,5-difluorophenyl)prop-2-en-1-one) (48) and (2E,2'E)-1,1'-(2-hydroxy-4,6-dimethoxy-1,3-phenylene)bis(3-(3,4- difluorophenyl)prop-2-en-1-one) (49) were evaluated and found to be possessing significant activity against cancer cell lines. The molecular docking analysis revealed that this compound successfully inhibited the xanthine oxidase⁵⁸. Novel Chalcone-1,2,3-triazole-azole derivate, (E)-1-(4-(3-(4-(((1,3,4-Thiadiazol-2-yl)thio)methyl)-1H-1,2,3-triazol-1-yl)propoxy)phenyl)-3-(3,4,5- trimethoxyphenyl)prop-2-en-1-one (50) was synthesized and evaluated against SK-N-SH (glioblastoma), EC-109 (oesophageal) and MGC-803 (gastric) cell lines. The compound was found to be active against SK-N-SH cell line with a better IC₅₀ value⁵⁹. Novel ligustrazine-chalcone derivative (51) was found to be active against triple-negative breast cancer and induced apoptosis through the cell cycle arresting at G0/G1 phase⁶⁰. Chalcone incorporated quinazoline derivatives were designed and evaluated against various cancer cell lines and the compound, (E)-1-(2-Fluoro-4-(trifluoromethyl)phenyl)- 3-(4-(quinazolin-4-ylamino)phenyl)prop-2-en-1-one (52) was found to be effective against A549 (lung), HT-29 (colorectal), MCF-7 (breast) and A375 (skin) cancer cell lines⁶¹. 

Novel Benzimidazole-Pyrazoline Hybrid Molecule containing chalcone derivative, Ethyl 2-(2-cinnamoyl-1H-benzo [d]imidazol-1-yl)acetate (53) also exhibited significant anticancer activity against the breast cancer cell line, MDA-MB-231 with a better IC₅₀ value⁶². The anticancer potential of the compound, (E)-1-(4-(3-chlorocyclopenta-1,3-dien-1-yl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d]imidazol-2-yl)-3-(4- chlorophenyl)prop-2-en-1-one (54) was evaluated by an in silico experiment, using epidermal growth factor receptor as target and found to be more potent than doxorubicin for hepatocellular carcinoma⁶³. The anticancer and apoptotic potential of the compound, 1-(4-(4-(2-Methoxyethyl) piperazin-1-yl)phenyl)- 3-(naphthalen-2-yl)prop-2-en-1-one (55) was evaluated against A549 lung cancer cell line using an MTT assay. It was found to be highly active and exhibited significant apoptosis, determined by the flow cytometry analysis. The molecular docking studies against vascular endothelial growth factor receptor-2 and caspase enzymes exhibited better binding energy, which revealed that this compound was an anticancer agent with significant binding interactions⁶⁴.

Antioxidant activity of chalcones and their derivatives

Bis-Chalcones (56,57) were synthesized by using the Claisen-Schmidt condensation reaction and the free radical scavenging potential of these compounds was evaluated using FRAP assay. These compounds exhibited better activity with significant EC₅₀ values, which was due to the presence of chlorine substitution in the aromatic ring²¹. Hesperidin methyl chalcone (58) increased the production of reactive oxygen species and showed significant antioxidant activity, determined by the FRAP and ABTS radical scavenging activity⁶⁵. 

Figure 5: Compounds possessing anticancer (48-55) and antioxidant (56-58) activities

The in vitro antioxidant potential of the coumarin clubbed chalcone hybrid (59) was evaluated by using DPPH free radical scavenging method. The evaluated compound was found to be having greater antioxidant potential, due to the presence of electron releasing 2- OH group in its structure⁶⁶. Alkyl-substituted pyrazine derivative of chalcone (60) exhibited significant radical scavenging activity, determined by DPPH assay. Similar to the previously discussed compound, the activity was due to the presence of a hydroxyl group in the aromatic core unit⁶⁷. The antioxidant activity of the compound, 3-(3,4-dimethoxyphenyl)-1-(10-dodecyl phenothiazin-2-yl)prop-2-en-1-one (61) was evaluated using DPPH assay and found be having significant activity similar to the standard, ascorbic acid. The activity of this compound was due to the presence of the phenothiazine ring with its structure⁶⁸.

Anti-inflammatory activity of chalcones and their derivatives

A group of 2-methyl-4-phenyl quinoline-chalcone analogues (62-64) was designed and their anti-inflammatory potential was analysed. These potent compounds exhibited significant activity with better IC₅₀ values and were also found to be having cyclooxygenase-2 inhibitory activity²⁵. Chalcone derivative containing aryl-sulfonyl-piperazine fragment (65) was synthesized and evaluated its anti-inflammatory potential by using classical para-xylene-induced mice ear-swelling model and ELISA assays. It was found to be inhibiting the LPS-induced IL-6 and TNF-α release. The molecular docking studies also correlated with the in vitro and in vivo experimental results⁶⁹.

Conjugated indolyl chalcones (66,67) were afforded by the Knoevenagel condensation of 3- cyanoacetylindoles with substituted 3-chloro-3-phenyl-propenals. The anti-inflammatory effect of these compounds was evaluated against egg albumin denaturation and found to be highly effective in heat-induced albumin denaturation inhibition⁷⁰. The antioxidant potential of (Е)-1-(2-Hydroxyphenyl)-3-(3-ethoxy-4-hydroxyphenyl)prop-2-en-1-one (68) was evaluated against lipopolysaccharide-induced production of anti-inflammatory cytokines interleukin-6 inhibition and exhibited significant activity. The molecular docking results with the best binding affinity were also correlated with the experimental results⁷¹.

Antidiabetic activity of chalcones and their derivatives

(E)-1-(2-Hydroxyphenyl)- 3-(2-Hydroxy-3-Methoxyphenyl) Prop-2-En-1-One (69) was synthesized by means of Claisen-Schmidt condensation and evaluated its potential against streptozocin induced diabetic mice. Postprandial hyperglycaemia along with blood glucose level was reduced significantly in a dose-dependent manner. The potent activity of this compound was due to the presence of electron-donating substituent in this structure²⁶. (E)-1-(4′-Aminophenyl)-3-(3,5-dimethoxy,4-hydroxyphenyl) prop-2-en-1-one (70) and (E)-1-(4′-Aminophenyl)-3-(4-isopropyl phenyl) prop-2-en-1-one (71) were afforded by the reaction of 4-aminoacetophenone and aromatic aldehyde under microwave conditions at 180 W for 10-15 min. The antidiabetic potential of these compounds was tested using albino wrister rats and found to be exhibiting a significant effect by reducing blood glucose levels. The binding affinity of compounds with the diabetic targets also revealed the potent activity of these compounds, determined by molecular docking studies⁷². The antidiabetic potential of coumarin-chalcone hybrids, 4-(4-hydroxy-2-oxo-2H-chromen-8-yl)-6-methyl-5-(3-(3,4,5-trimethoxyphenyl) acryloyl)-3,4-dihydropyrimidin 2(1H)-one (72) and 4-hydroxy-8-(6-methyl-2-thioxo-5-(3-(3,4,5-trimethoxyphenyl) acryloyl)-1,2,3,4-tetrahydro pyrimidin4-yl)-2H-chromen-2-one (73) were determined by means of both in vivo and in silico studies. The in silico analysis of these compounds against the diabetic targets exhibited very low binding energy and showed better interactions. Based on the in silico molecular docking results, the in vivo studies were carried out and found to be exhibiting potent antidiabetic activity against streptozocin-induced diabetic animals with a significant reduction in blood glucose levels⁷³. 

Figure 6: Compounds possessing antioxidant (59-61), anti-inflammatory (62-68) and antidiabetic (69-70) activities

Neurodegenerative activity of chalcones and their derivatives

The neurodegenerative activity of the chalcone analogue (74) synthesized from 7-methoxy-3,4-dihydronaphthalen1(2H)-one and aromatic aldehydes under basic conditions were evaluated and found to be the potent neuro-therapeutic compound against glutamate-induced cell death²³. The acetylcholinesterase inhibitory activity of the novel chalcone namely, (E)-N-(4-(3-(pyridin-3-yl)acryloyl)phenyl)quinoline-3- carboxamide (75) was evaluated by using an Ellman’s spectrophotometric method. The potent activity with a better IC₅₀ value of this compound was due to the presence of the 3-pyridine group in its structure. The in silico studies were also correlated with the in vitro results, which exhibited better binding energy with better interactions²⁴. µ-calpain and cathepsin β inhibitory activities (responsible for Alzheimer’s disease) of various chalcones were evaluated by using a fluorometric m-calpain and cathepsin B assay. Among the various derivatives, the compounds (E)-1-(2,4-dihydroxy phenyl)-3-(4- hydroxynaphthalen-1-yl)prop-2-en-1-one (76) and (2E,4E)-5-(4-Hydroxy-3-methoxyphenyl)-1-(4- hydroxyl phenyl)penta-2,4-dien-1-one (77) were exhibited potent neuroprotective effect by inhibiting the enzymatic activities at the cellular level, followed by the p25 formation, tau phosphorylation and insoluble Ab peptide formation reduction⁷⁴.

Quinoline containing chalcone derivatives (78,79) was designed and evaluated as cholinesterase inhibitors by using Ellman’s spectrophotometric method. The in vitro results showed that these compounds exhibited better cholinesterase inhibitory activity with better IC₅₀ values. The molecular docking results also revealed that these compounds had shown better binding affinity towards the cholinesterase targets and this was due to the presence of methyl and methoxy groups in side chain and dioxane ring in this structures⁷⁵. The chalcone-triazole hybrids were synthesized and the neuroprotective potential was evaluated using SH-SY5Y cells. The compounds, (E)-3-(3,4-dimethoxyphenyl)-1-(4-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (80) and (E)-4-((1-(4-(3-(3,4-dimethoxyphenyl) acryloyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (81) were found to be having potent neurodegenerative potential, especially for Alzheimer’s activity⁷⁶.

Figure 7: Compounds possessing antidiabetic (71-73) and neurodegenerative (74-81) activities

The anti-butyrylcholinesterase activity of the compound, (E)-3-(3-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butoxy)phenyl)-1-(2-hydroxyphenyl)pro p-2-en-1-one (82) was evaluated by using modified Ellman assay. This compound significantly inhibited self-induced and Cu²⁺-induced Aβ1-42 aggregation. The exhibited results were found to be correlated with the molecular docking studies⁷⁷. Chalcone-Vitamin E-donepezil hybrid, (E)-1-(3,6-dihydroxy-2,4-dimethoxyphenyl)-3-(4-((6-(ethyl(2- methoxybenzyl)amino)hexyl)oxy)phenyl)prop-2-en-1-one (83) was obtained by treating (E)-3-(4-(6-(ethyl(2-methoxybenzyl)amino)hexyloxy)- phenyl)-1-(6-hydroxy-2,4-dimethoxy-3-(methoxymethoxy)phenyl)prop-2-en-1-one with 10 % HCl and the anticholinesterase inhibitory activity of this compound was determined by using Ellman assay. This compound exhibited significant acetylcholinesterase inhibitory activity, along with the inhibition of self-induced and Cu²⁺-induced Aβ1-42 aggregation. The molecular docking results also correlated with the experimental results, found to be a potent derivative for Alzheimer’s disease⁷⁸.

Vitiligo treatment of chalcones and their derivatives

Novel isoxazole chalcone derivatives, 1-(4-((3-(3,4-Difluorophenyl)isoxazol-5-yl)methoxy) phenyl)-3-phenylprop-2-en-1-one (84) and 1-(4-((3-(2,3-Dihydrobenzo [b][1,4]dioxin-6-yl)isoxazol-5-yl)methoxy)phenyl)-3-phenylprop-2-en-1-one (85) exhibited a stronger activity on melanogenesis and found to be the potent compounds for the treatment of vitiligo²⁷. 2′,3,4, 4′-tetrahydrochalcone analogue (86) also exhibited better melanogenesis and was found to be a potent candidate for vitiligo treatment⁷⁹.

Antileishmanial activity of chalcones and their derivatives

The antileishmanial activity of chalcone derivative (87) was evaluated against Leishmania infantum promastigotes and found to be highly effective with better IC₅₀ value. The molecular docking studies also correlated with this results⁸⁰. The nitro-analogue, 3-nitro-2’,4’,6’- trimethoxychalcone (88) was found to be a potent broad-spectrum antileishmanial drug candidate, determined by the molecular modelling studies⁸¹. ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl) prop-2-en-1-one) (89) was synthesized, evaluated and found to be effective against promastigote and amastigote forms of L. amazonensis. It was found to be a potent compound with a better IC₅₀ value. The molecular docking studies also exhibited that the compound had more hydrogen bond interactions with the ARG enzyme and correlated with the experimental results⁸². Similarly, the antileishmanial activity of another chalcone derivative (90) was evaluated against L. amazonensis and was found to be exhibiting potent activity⁸³. 

Figure 8: Compounds possessing neurogenerative (82-83), vitiligo treatment (84-86) and antileishmanial (87-90) activities

Conclusion

Being an important class of compounds in synthetic and pharmaceutical chemistry, the enormous biological application of chalcones and their derivatives are summarized in this review. The compounds possessing different biological applications including antimicrobial, anticancer, antimalarial, antitubercular, antioxidant, anti-inflammatory, antileishmanial, antidiabetic, neuroprotective, anti-Alzheimer, melanin formation and anti-vitiligo properties were discussed. These types of compounds were designed and synthesized by means of Claisen-Schmidt condensation, Knoevenagel condensation, crossed aldol condensation and Aldol condensation using microwave-assisted, ultrasonic-mediated and also by conventional synthetic approaches. Especially, these derivatives exhibit anticancer potential in a greater manner and found to act as tubulin polymerization inhibitors, microtubule-targeting agents, apoptosis inducers via various pathways, epidermal growth factor and vascular endothelial growth factor receptor inhibitors. Currently, these derivatives are widely designed and found to be possessing antimicrobial, anticancer and neuroprotective properties. These compounds also play a vital role in coordination chemistry and also in the development of chalcone-based hybrid molecules. Thus, by developing and implementing various greener mediated synthetic approaches, the novel derivatives of this moiety can be developed and tried for numerous applications in the future.

Acknowledgement

We thank the Management and Dr. G. Murugananthan, Principal of our college for giving constant support and encouragement for writing this review. 

Authors Contributions: All the authors have contributed equally. 

Funding: Nil.

Conflicts of Interests: The authors declare no conflict of interest.

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