SYNTHESIS AND ANTIBACTERIAL EVALUATION OF NEW FLAVONOID DERIVATIVES FROM 4 , 6-DIACETYL RESORCINOL

In order to check the antibacterial potential of bischalcones derived from 4,6-diacetyl resorcinol, a number of chalcone derivatives were synthesized by condensation with appropriate aromatic aldehydes. Out of these compounds 3b-i, 4a and 4b showed a good antibacterial activity. Methylation of the two chelated hydroxyls reduced the activity. However, oxidative cyclization of 3a and 3b resulted in compounds 4a and 4b which were found to be considerably active. The alternative method of synthesis of 4a and 4b via Baker-Venkatararnan rearrangement did not succeed.


Introduction
Flavonoids have attracted considerable attention due to their marked physiological activity and distinct functions'-6.Flavonoidal derivatives-chalcones, flavanones and flavones, form a large group of naturally occurring organic compounds and possess wide range of pharmacological actions including antimicrobial action7-'*.
In view of their important medicinal properties it was considered worthwhile to synthesize some new flavonoidal derivatives.

Results and Discussion
The title compounds were synthesized according to the Scheme-I.The starting material was 4,6- diacetyl resorcinol (I), which was synthesized from resorcinol and acetic anhydride in presence of anhydrous zinc chloride using Nencki's method.The diacetyl derivative (1) was condensed with different aromatic aldehydes in presence of potassium hydroxide to give 9 bischalcones (3a-i).
Bischalcones were cyclized by heating in dimethylsulphoxide solution containing traces of iodine to give flavones (4a-b).An alternate route to synthesize the flavones consisted in preparing the ester derivatives of 4,6-diacetyl resorcinol with different aromatic acids in dry pyridine in presence of phosphorous oxychloride, which could be converted to P-diketones through the well known Baker-Venkataraman rearrangement followed by cyclization to give the corresponding flavones.
However, all the attmepts in this direction were unsuccesshl and it could not be possible to proceed beyond diester stage; seven diester derivatives (5a-g) were synthesized.The dimethyl ether derivative (2) was prepared by refluxing (1) with dimethylsulphate in dry acetone in the presence of anhydrous potassium carbonate.It (2) was condensed with different aromatic aldehydes to give seven bischalcone derivatives (6a-g).The structures assigned to the compounds were supported by the results of elemental analysis as well as 'H NMR and Mass spectral data (Table -1).

Is 4 , 6 -
= singlet; d = doublet; dd = double doublet; t =triplet; q = quatret; m = multipletAntibacterial activityAll the twenty eight newly synthesized compounds were evaluated for in-vitro antibacterial activity against Staphylococcus aureus and Escherichia coli, at a concentration of 100pgIml by agar diffusion (cup-plate) method13.The zone of inhibition of the standard sulpharnethoxazole was 15-20 mm against S.aureus and E.coli.Compounds 3e and 3i (zone of inhibition 11-16 rnrn) were highly active against S.aureus.Compounds 4a and 3b (zone of inhibition 8-10 mrn) showed significant activity and compound 3c, 3d, 3f, 3g, 3h and 4b (zone of inhibition 5-7 mm) exhibited appreciable activity against S.aureus.Rest of the compounds were insignificant in their action.EXPERIMENTALMelting points are uncorrected and were recorded in liquid paraffin bath using open end capillaries.'H NMR spectra were recorded on a Bruker 300 MHz NMR spectrometer (internal reference-tetramethyl silane) and Mass spectra were recorded on a JEOL JMS-DX 303 instrument.Thin layer chromatography was performed on silica gel G (Merck).Dry solvents were used throughout.Diacetyl resorcinol(1)    To a solution of resorcinol (12gm) in acetic anhydride (16 ml), hsed zinc chloride was added.The reaction mixture was heated at 142" for 15 minutes.A viscous red solution so obtained was cooled to room temperature and then stirring with a mixture of HCl and water (1 : 1) gave an orange red crystalline compound, which was crystallized from methanol to give needles of 1.Dimethyl ether derivative (2) of 1Compound 1 (2.5mrnole; 4.85 g) was taken in dry acetone (100 ml) and after adding anhydrous potassium carbonate (1 1.25 g) and dimethyl sulphate (5 m o l e ; 4.8 ml), the reaction mixture was refluxed for 6 hours on a water bath.The contents were then filtered, concentrated to a small volume and poured onto crushed ice when a solid mass separated out which was filtered and washed with water.It was crystallized to give shiny needles of 2 (it did not give any colour with ethanolic ferric chloride solution).Bischalcones (3a-i) (6a-g)To a solution of 112 (5 rnrnole) in ethanol (20 ml) was added aromatic aldehyde (10 m o l e ) and a solution of potassium hydroxide (3 g) in distilled water (5 ml) with stirring.The contents were stirred for 2 hours and left overnight at room temperature and then poured into cold water and acidified with HCl when a solid mass separated out which was filtered, washed with water, sodium bicarbonate solution (2% w/v in water) and again with water.It was crystallized to give 3a-i (It gave a violet colour with alcoholic ferric chloride solution and a red colour with conc.sulphuric acid) and 6a-g (It gave a red colour with conc.sulphuric acid and no colour with alcoholic ferric chloride solution).