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antimicrobial evaluation of some novel bis-heterocyclic chalcones

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Synthesis and antimicrobial evaluation of some novel bis-heterocyclic chalcones from cyclic imides under microwave irradiation
Ravindra S. Dhivare1* and Shankarsing S. Rajput2
Chem Sci Rev Lett 2015; 4(15): 937-944     Article CS05204609    http://chesci.com/articles/csrl/v4i15/19_CS05204609.pdf

Synthesis of a new series of bis-heterocyclic chalcone derivatives has been reported. The condensation proceeded by the one pot reaction of N-phenyl succinimides and 4-hydroxy-3-methoxy benzaldehyde in presence of neutral alumina under microwave irradiation. The advantages of this method are high yield, shorter reaction time and simple workup procedure. Most of the synthesized compounds have shown moderate to significant antimicrobial activity against different microbial strains.

Chalcones and cyclic imides perform a significant title role in the heterocyclic synthesis containing oxygen, nitrogen and sulphur groups. Cyclic imides [1] like succinimides [2] [3] [4], maleimides [5], glutarimide [6], itaconimide[7] and phthalimides[8] showed the defensive antibacterial [9], antifungal activities. Cyclic imides exhibited the CNS anxiolytic and anti-depressive [10], brain metabolism [11], nephrotoxic [12], antiviral [13], anticonvulsant [14] electroshocks [15] , muscle relaxant [16], anti-mutagenic [17], analgesic [18], anxiety and depression [19], myeloperoxidase induction [20], antiproliferative [21], seedling growth [22] activities. The substituted heterocyclic imides were developed from cyclic anhydrides [23], formamide [24], trifluoroacetylation [25], triethylamine [26], hydroxylamine [27], thalidomide biotin [28] , pyrolidine triones [29] reagents and bis-heterocyclic analogs [30] by microwave synthesis. Bis-chalcones are the pioneer flavonoids of heterocycle ancestor containing carbon stuck between α, β- unsaturated aromatic rings and carbonyl carbons. These are prepared by the condensation [31] of the substituted ketones and aldehyde groups [32] [33]. The chalcone showed significant cytotoxic activities against antimicrobial [34] , cell line and breast cancer [35], anti-oxidant [36], bovine lens aldose reductase [37], tumor-genesis activities [38]. The chalcones are synthesized by utilizing a number of synthetic routes like solid phase Claisen-Schemdit, Cross-Aldol condensation, acid catalyst [39], coupling reaction [40], Knoevenagel condensation [41] and microwave assisted synthesis.

Preparation of substituted bis-heterocyclic chalcones: The N-substituted Phenylpyrrolidine-2, 5-diones or N-phenyl succinimides are conventionally synthesized by succinic anhydride and substituted anilines. Then afforded succinimides were employed for the preparation of bis-chalcone derivatives by microwave synthesis. The experimental method of conventional to microwave synthesis is schematically represented in figure 1

Figure 1 Experimental design of conventional to microwave method

General Procedure for the Synthesis of N-phenyl-pyrrolidine-2, 5-dione or N-Phenyl Succinimides

To accomplish the work succinic anhydride (0.1 moles) benzene was added and heated under reflux with constant stirring for 15 to 20 min till the solution becomes clear. Into this solution the primary aromatic amines (0.2 moles) in 5 ml benzene was slowly poured with constant stirring for 15- 20 min till the solution becomes homogenized. On the vaporization of benzene amorphous powder of 3-(N-phenyl) propanoic acid was obtained. Further the mixture of 3- (N-phenyl) propanoic acid and acetyl chloride (0.9 moles) was reflux for 15-20 min by thoroughly evolution of HCl fumes. The reaction mixture was cooled at room temp the solid product was obtained and recrystallized by ethanol as shown in the scheme 1

General procedure for the synthesis of bis-chalcones derived from N-phenyl succinimides

The bis-chalcones (6a-j) derivatives were synthesized by the mixture of 0.1 moles of N-phenyl succinimides (4a-j) and 0.2 mole of 4-hydroxy-3-methoxy benzaldehyde in 2 gm of neutral Al2O3 under microwave supported solvent free condition on 640W power for 5-8 min. The developed compounds were recrystallized from ethanol (Scheme 2)

Chemistry: The starting compounds of bis-chalcones 6a-j were prepared by the reaction of substituted N-phenyl-pyrrolidine-2, 5- dione 4a-j using 4-hydroxy-3-methoxy benzaldehyde. The series of 3,4-bis(4-hydroxy-3-methoxy benzylidene)-Nphenylpyrrolidine-2,5-diones 6a-j were synthesized in reasonable yields by the microwave irradiation of cyclic imides 4a-j with vanillin in presence of neutral alumina in solvent free condition. The structure of bis-chalcones was confirmed by IR, 1H NMR and elemental analysis.

Antimicrobial activities (4a-j and 6a-j): All the synthesized compounds 4a-j and 6a-j were screened for their antibacterial activity against gram positive bacteria Bacillus subtilis (MCMB-310) and gram negative bacteria Escherichia coli (MCMB-301) using DMF solvent as shown in the graph -1. And antifungal activities against Candida albicans (NCIM-3471) and Aspergillus niger (NCIM- 545) strains using DMSO solvent revealed in the graph – 2. All the results of the synthesized compounds were carried out by the triplicate format N=3 with Mean ± SD. The statistical significance was carried out by one way ANOVA and confirmed by Dunnett multiple comparisons test performed the standard drugs against synthesized compounds. P value < 0.05 was considered as statistically significant remarked by *p<0.05, **p<0.01, ***p<0.001 compared to standard groups. The calculated data were tabulated (not shown).

Table 1 Antimicrobial activities of Bis-chalcones      Bacillus subtilis, Escherichia coli, Candida albicans, Aspergillus niger

Graph 1 Antibacterial activities of 4a-j and 6a-j (B.S. and E.C.) Mean±SD

Graph 2 Antifungal activities of 4a-j and 6a-j (C.A. and A.N.) Mean±SD

Conclusion An entire new series of bis-heterocyclic chalcones containing 4-hydroxy-3-methoxy benzylidene nucleus have been synthesized in one pot and facile manner from cyclic imides in good yield. A good number of the synthesized bischalcone 6a-j showed noticeable synergistic antifungal activities against Candida albicans and Aspergillus niger fungal strains.