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INTRODUCTION Chalcone is a generic term given to compounds bearing the 1, 3- diphenyl-2-propen-1-one framework and belong to the flavonoid family. 1-3 The name “Chalcones” was given by Kostanecki and Tambor. 4 These compounds are also known as benzalacetophenone or benzylidene acetophenone . Chalcones are -unsaturated ketone containing the reactive ketoethylenic group –CO-CH=CH-. These are coloured compounds because of the presence of the chromophore - CO-CH=CH-, which depends in the presence of other auxochromes.Chemically they are open-chain flavonoids in which the two aromatic rings are joined by a three carbon α,β- unsaturated carbonyl system. Chalcones are abundantly present in nature starting from ferns to higher plants. 5 and a number of them are polyhydroxylated in the aryl rings. In plants, chalcones are converted to the corresponding (2S)-flavanones in a stereospecific reaction catalyzed by the enzyme Chalcone isomerase. This close structural and biogenetic relationship between chalcones and flavanones explains why they often co-occur as natural products. General structure of Chalcone All the chalcones give pink coloration with concentrated sulphuric acid in Wilson’s test. 6 and when a phenolic hydroxyl group is present, they give violet coloration with alcoholic ferric chloride solution. Chalcones on heating with traces of iodine in dimethyl sulphoxide (DMSO) for two hours give the corresponding flavones. Chalcones were converted into the corresponding flavonols by their oxidation using hydrogen 1

Chalcone Thesis

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Page 1: Chalcone Thesis

INTRODUCTION

Chalcone is a generic term given to compounds bearing the 1, 3-diphenyl-2-propen-1-one framework and belong to the flavonoid family.1-3 The name “Chalcones” was given by Kostanecki and Tambor.4 These compounds are also known as benzalacetophenone or benzylidene acetophenone . Chalcones are -unsaturated ketone containing the reactive ketoethylenic group –CO-CH=CH-. These are coloured compounds because of the presence of the chromophore -CO-CH=CH-, which depends in the presence of other auxochromes.Chemically they are open-chain flavonoids in which the two aromatic rings are joined by a three carbon α,β-unsaturated carbonyl system. Chalcones are abundantly present in nature starting from ferns to higher plants.5 and a number of them are polyhydroxylated in the aryl rings. In plants, chalcones are converted to the corresponding (2S)-flavanones in a stereospecific reaction catalyzed by the enzyme Chalcone isomerase. This close structural and biogenetic relationship between chalcones and flavanones explains why they often co-occur as natural products. General structure of Chalcone

All the chalcones give pink coloration with concentrated sulphuric acid in Wilson’s test. 6 and when a phenolic hydroxyl group is present, they give violet coloration with alcoholic ferric chloride solution. Chalcones on heating with traces of iodine in dimethyl sulphoxide (DMSO) for two hours give the corresponding flavones. Chalcones were converted into the corresponding flavonols by their oxidation using hydrogen peroxide in methanolic sodium hydroxide solution and these flavonols showed a characteristic greenish yellow fluorescence in ethanolic solution as well as with concentrated sulphuric acid..Chalcones as Drugs

Chalcones are popular intermediates for synthesizing various heterocyclic compounds (Rajendra Prasad et al., 2008). The compounds with the backbone of chalcones have been reported to possess various biological activities such as antimicrobial, anti-inflammatory, analgesic, antiplatelet, antiulcerative, antimalarial, anticancer, antiviral, antileishmanial, antioxidant, antitubercular, antihyperglycemic, immunomodulatory, inhibition of chemical mediators release, inhibition of leukotriene B4, inhibition of tyrosinases and inhibition of aldose4 reductase activities (Rajendra Prasad et al., 2008). The presence of a reactive α,β- unsaturated keto function in chalcones is found to be responsible for their biological activities (Rajendra Prasad et al., 2008).

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SYNTHETIC METHODS OF PREPARING CHALCONES

1) CLAISEN-SCHMIDT REACTION

The chalcones (3) were synthesized by a base catalyzed Claisen–Schmidt condensation reaction of substituted acetophenone (1) and aromatic aldehyde (2).9-12

Scheme 1 : The Claisen-Schmidt Reaction

2) The Allan-Robinson Condensation

The Allan-Robinson condensation method is mainly to synthesize flavones. The condensation of 2,4,6-trihydroxyacetophenone (4) with aromatic anhydrides (5) in the presence of the salt of the same acid at oil bath temperature will produce corymbosin (6) (Fukui et al., 1968).

Scheme 2 : The Allan-Robinson Condensation

3) Synthesis of Chalcones via Microwave Irradiation

Chalcones were prepared by Claisen- Schmidt Condensation of methyl Ketones (7) with several aromatic aldehydes (8) in presence of aqueous solution of sodium hydroxide using microwave irradiations.58

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Scheme 3 : Chalcone synthesis via microwave irradiation

4) Synthesis of Chalcone using Borontrifluoride-etherate

Narender and Reddy (2007) developed a new methodology by using BF3- Et2O to synthesize several substituted chalcones. The advantages of this method over the existing methods are high yields, simple work-up, short reaction times, no side reactions, and separation is needed to get the products. This method is solventfree reactions and applicable for reactions involving liquid reactants which are base sensitive functional groups such as esters and amides.

Scheme 4: Synthesis of O-acylated and N-acylated chalcones using BF3-Et2O

A condensation reaction between O-acylated (10) or N-acylated acetophenone (13) and the respective aromatic aldehyde (11) or (14), produced Oacylated (12) or N-acylated chalcones (15) in high yields by using BF3-Et2O (Narender and Reddy, 2007) as shown in Scheme 2.5.

5 The Von-Konstanecki Method

This is a general method for synthesizing flavones which involves a reaction of 2 methoxybenzoate (16) and acetophenone in the presence of sodium to form (18) as shown in Scheme 5. The diketone compound (18) was formed via Claisen condensation. and elimination of water formed flavones (19) (Nakanishi, 1975).

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Scheme 5 : The Von-Konstanecki Method

6) Friedel-Crafts Acylation

Besides the Claisen-Schmidt reaction, chalcones can also be synthesized by direct Friedel-Crafts acylation of a phenol. In this approach the phenol becomes the A-ring while the acylating agent provides both the B-ring carbons and the three carbon bridge to form C6-C3-C6 unit (Bohm, 1998). Friedel-Crafts acylation of 2,4-dimethyl-1,3,5-triolbenzene (20) with 3- phenylpropionyl chloride (21) gave 2’,4’,6’-trihydroxy-3’,5’-dimethylchalcone (22) (Bohm, 1998).

Scheme 6 : Friedel-Crafts acylation producing chalcone

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THERAPEUTIC POTENTIAL OF CHALCONES

Chalcone is a unique template that is associated with several biological activities and is well known intermediates for synthesizing various heterocyclic compounds.7 They are secondary

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metabolites of terrestrial plants, precursors for the biosynthesis of flavonoids. The introduction of a halogen into the benzenoid part of these α, β-unsaturated ketones enhances their biological activity.8 The compounds with chalcone as backbone have been reported to possess varied biological and pharmacological activities, including antimicrobial, anti-inflammatory, analgesic, cytotoxic, antitumor, antimalarial, antitubercular, antiviral, anti-HIV, antiulcerative, antileishmanial, antioxidant, antiprotozoal, antihistaminic, immunomodulatory, anticonvulsant, antihyperglycemic, antihyperlipidemic and antiplatelet activities. Thus chalcones continue to attract considerable scientific attention because of their association with a variety of biological activities. Given below is a brief account of various modifications reported on chalcones, which resulted in a variety of biological and pharmacological activities.

Antimicrobial Activity

K.L. Lahtchev et al.9 synthesized chalcones(23) showing antifungal activity, antitubercular.

Nielsen et al.10 described the bioisosteric replacement of the essential 4'-hydroxy group in the hydroxychalcones (24) with bioisosters of varied degrees of acidity which resulted in both more potent and more soluble compounds. Exchanging the hydroxyl group, particularly with a carboxy group resulted in a potent compound with a high aqueous solubility. Further optimization and SAR analysis resulted in soluble and potent carboxychalcones having dibromo or trifluoromethyl substitution on B-ring . The MIC values for these compounds were found to be 2 μM and 40 μM respectively when tested against the Gram-positive bacterium Staphylococcus aureus. A dibromo or trifluromethyl substitution on B-ring was found to enhance the lipophilic character, while the carboxy group on A-ring contributed to the required aqueous solubility

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Liu et al.11 synthesized chalcones-imidazole (25) derivatives which showed antimicrobial activity

Ngaini et al.12 synthesized hydroxylated Chalcones (26) possess antimicrobial activity against E.coli.

Bandgar et al.13 synthesized β-chloro vinyl chalcones (27) as inhibitors of TNF-a and IL-6 with antimicrobial activity.

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Tomar et al.14 have synthesized chalcones (28) containing piperazine or 2,5-dichlorothiophene moiety which shows antimicrobial activity.

Bakht et al.15 have synthesized oxadiazole derivatives( 29) shows antimicrobial activity.

Solankee et al.16 prepared S-triazine based chalcones (30) and their derivatives as potent antimicrobial agents.

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Babashaheb et al.17 synthesized olefin Chalcones (31) which showed antitumor, antioxidant and antimicrobial activities.

Patel et al.18 have prepared chalcones (32) which possess antimicrobial activity.

Nagwanshi et al.19 have synthesized Chalcones (33) from acetyl furan shows antimicrobial actvity

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Chauhan et al.20 have synthesized Chalcones (34) derivatives of indole nucleus which shows antimicrobial activity.

Patel et al.21 which have synthesized pyridine analogs of chalcones (35) and shows antimicrobial activity.

Banday et al.22 synthesized chalconyl derivatives of pregnenolone (36) and their evaluation as antimicrobial agents against various microbial strains is reported

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Jin et al.23 synthesized chalcone derivatives containing 2-thioxo-4- Thiazolidinone (37) which showed antimicrobial activity.

Adibi et al.24 synthesized allylic substitution of chalcones (38) that exhibit antimicrobial and antioxidant activities.

Asiri et al.25 synthesized bis Chalcones derived fron thiophene (17) that possess antimicrobial activity.

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Zheng et al.26 synthesized Chalcone Heterocyclic Chalcones (40) Derivatives Bearing Thiofuran, Furan,and Quinoline Moieties which showed antimicrobial activity.

Sugamoto et al.27 synthesized chalcones (41) bearing prenyl or geranyl groups from Angelica keiskei that showed antimicrobial activity.

Mokle et al.28 synthesized Chalcones (42) from 2-Chloro-8-methoxy-quinoline-3-carbaldehyde that showed antimicrobial activity.

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Liaras et al.29 synthesizes thiazole-based Chalcones (43) which exhibit antimicrobial activity.

Sumathi et al.30 synthesized NLO Properties of Chalcone (44) Metal Complexes which showed antimicrobial activity.

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Bandgar et al.31 which have synthesized pyrazole chalcones (45) which shows anti-inflammatory, antioxidant and antimicrobial activity.

Antibacterial and Antifungal Activity

Lopez et al.32 synthesized Chalcone Derivatives (46) with Inhibitory Properties Against Polymers of the Fungal Cell Wall.

Hussain et al.33 synthesized novel 3-[4-(1H-imidazol-1-yl) phenyl]prop-2-en-1-ones (47) showing Anti-oxidant, anti-fungal and anti-leishmanial activities

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Doble et al.34 synthesized Chalcones (48) possessing Antimycobacterial activiy

Konieczny et al.35 have synthesized oxathiolone fused Chalcones (49) which possess antifungal activity.

Budhiraja et al.36 prepared naphthalene, furan and pyrrole based chalcones (50) Which shows show antibacterial, antifungal, antitumour and anti-inflammatory activity.

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Raj et al.37 which have synthesized heterocyclic chalcones (51) and shows antiproliferative, antioxidant, antibacterial, antifungal, and antiviral properties

Hamdi et al.38 synthesized coumarinyl chalcones (52) and substituted chromeno[4,3-c]pyrazol-4(1H)-ones that showed antibacterial and DPPH radical scavenging activities

Bukhari et al.39 synthesized pyrazolobenzothiazine-based chalcones (53) that exhibit antibacterial activity.

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Hussain et al.40 synthesized Bis- Chalcones (54) derivatives which possessed antibacterial and antifungal activities against E.coli, P.aeruginosa and C.albicans with MIC -12.5µg/ML.

Kraus et al.41 isolated littorchalcone (55) from the aerial parts of V . littoralis H.B.K which exhibit antibacterial activity.

Konduru et al.42 synthesized Chalcone (56) Based Sulfones which showed antibacterial and antifungal acticvity.

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Jayashree et al.43 synthesized 3-Methyl Chalcones (57) which possess antibacterial and antioxidant activity.

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kumar et al.44 synthesized ruthenium(II) Chalcone Complexes (58) which exhibited antifungal activity.

kumar et al.45 Synthesized 2’-hydroxy Chalconate (59) Complexes of ruthenium (II) were found to be active against bacteria such as E.coli, Salmonella typhi and fungi Aspergillus niger.

Antitubercular Activity

Patel et al.46 which have synthesized 1-(4-((E)-3-arylacryloyl) phenyl)-3,4-dibromo-1Hpyrrole- 2,5-diones (60) exhibiting antituberculosis activity.

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Chiaradia et al.47 have synthesized chalcones (61) as efficient inhibitors of Mycobacterium tuberculosis protein tyrosine phosphatase PtpA .

Yadav et al.48 synthesized Chalcones (62) that enhance antitubercular activity.

Antimalarial Activity

Hayat et al.49 synthesized chloroquinoline based chalcones (63) which showed antimalarial activity.

Sharma et al.50 synthesized Substituted quinolinyl chalcones (64) and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37RV and antimalarial activity against NF-54 strain of Plasmodium falciparum.

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Antiamoebic activity

Budakoti et al.51 synthesized chalcones (65) having antiamoebic activity against HM1:1MSS Stain of E.histolytica.

Anti-HIV Activity

Sharma et al.52 synthesized 3-keto salicylic acid chalcones (66) as novel HIV-1 integrase inhibitors

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Anticancer Activity

Mohamed et al.53 synthesized a Novel Series of Chalcones (67) Incorporated Pyrazole Moiety that exhibit anticancer and antimicrobial activity.

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