In-vitro anticancer evaluation of newly designed and characterized tri/tetra-substituted imidazole congeners- maternal embryonic leucine zipper kinase inhibitors: Molecular docking and MD simulation approaches.

Our cascading attempt to develop new potent molecules now involves designing a series of imidazole derivatives and synthesizing two sets of 2,4,5- tri-substituted (4a-4d) and 1,2,4,5-tetra-substituted (6a-6d) imidazole by the principle of Debus-Radziszewski multicomponent synthesis reaction. The structures of the obtained compounds were confirmed by 1H/13C NMR, FT-IR, elemental analysis, purity and the retention time was analyzed by HPLC. Based upon the binding affinity in the molecular docking studies, we have synthesized different imidazole derivatives from which compound 6c have been found to show more anti-proliferative activity by inducing apoptosis at a higher rate than the other compounds corroborating the in-silico prediction. The structure and crystallinity of compound 4d have been confirmed by single XRD analysis. The synthesized molecules were screened for their in vitro anti-cancer properties in triple negative breast cancer cell line (MDA-MB-231), pancreatic cancer cell lines (MIA PaCa-2) and oral squamous cell carcinoma cell line (H357) and results indicated that all the compounds inhibited the cell proliferation in a concentration-dependent manner at different time points. The compounds 4b and 6d were found to be effective against the S. aureus bacterial strain whereas only compound 4d fairly inhibited the fungal strain of T. rubrum with a MIC 12.5 µg/mL. Molecular docking study reveals good interaction of the synthesized compounds with known target MELK involved in oncogenesis having high binding profiles. The lead compound 6c was further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex.