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

Abstract

A library of 2,3-dihydroquinazolin-4(1H)-one derivatives (5 a-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 (IC 50 = 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.