Identification of Promising Biofilm Inhibitory and Cytotoxic Quinazolin-4-one Derivatives: Synthesis,Evaluation,Molecular Docking and ADMET Studies

摘要

A library of 2,3-dihydroquinazolin-4(1H)-one derivatives(5a-k)were synthesized in good yield by using 1-Ethyl-3-Methylimidazolium hydrogen sulphate(10 mol%)as a catalyst and were evaluated for their anti-biofilm,antimicrobial and cytotoxicity potential.Among the synthesized compounds,2-(4-(1H-1,2,4-triazol-1-yl)phenyl)-2,3-dihydroquinazolin-4(1H)-one(5d)and 2,3-dihydro-2-(2,4,6-trimethoxyphenyl)quinazolin-4(1H)-one(5j)displayed better anti-biofilm activity than fluconazole(IC50 = 40 μM)with IC_(50)values less than 30 μM.Compound 5d also appeared to be fungicidal against C.Albicans having MIC=33.5 μg/ml comparable with standard fluconazole(50 μg/ml).All the synthesized compounds were also evaluated for cytotoxic activity by using MTT assay against HeLa,A-549 and MDA-MB-231 cell lines.The compound 5d was found to be more potent against MDA-MB-231 and A549 cell lines(IC_(50)= 11 ± 2 μM and 34±8 μM respectively)than 5-fluorouracil(IC_(50)= 19 ± 3 μM and 51 ± 5 μM respectively).The compounds substituted with 6-methyl-4-oxo-4H-chromen-3-yl(5a),biphenyl(5c)and 2-hydroxy-5-bromophenyl(5e)were also found to be more potent against MDA-MB-231 cell lines(IC_(50)= 13 ± 3-14 ± 4 μM)than 5-fluorouracil.Molecular docking simulations were also carried out using secreted aspartyl protease(SAP5),pepA enzyme of C.albicans for biofilm inhibition and EGFR tyrosine kinase for cyto-toxicity studies.The study reveals that the compounds 5d and 5e can serve as an important lead moiety for biofilm inhibition and cyto-toxicity against MDA-MB-231 and A549 cancer cell-lines indicating their potential in the treatment of tougher fungal infections and breast and lung cancer.