Novel Pyrimidine Tethered Benzamide Derivatives as Potential Anticancer Agents: Synthesis, Characterization, Molecular Docking and In vitro Cytotoxicity Evaluation

Abstract

Current research work presents the synthesis, characterization, molecular docking study and in vitro cytotoxicity evaluation of novel pyrimidine-tethered benzamide derivatives as potential anticancer agents. The synthesis involved multi-steps procedure, including the synthesis of various chalcones (3a-t) with corresponding ketones (1 and 2) and substituted aldehydes (a-j), followed by pyrimidine amines (5a-t) with condensation of chalcones and guanidine and finally pyrimidinyl benzamide derivatives (8a-t) from compounds 5a-t coupling with acid chloride (7) using DIBAL-H. Synthesized compounds characterized by NMR spectroscopy and HRMS. The molecular docking studies were conducted against EGFR (6LUD) and CDK-4 (7SJ3) receptors, revealing distinct binding affinities influenced by substituent groups. Additionally, the cytotoxicity of the synthesized compounds was evaluated using the MTT assay against various cancer cell lines, including A-549 (non-small cell lung cancer), HCT-116 (colorectal cancer), PANC-1 (pancreatic cancer) and HaLa (cervical cancer), along with one normal human embryonic kidney cell line (HEK-293). Among the synthesized compounds, derivatives 8f and 8j exhibited the best anticancer activity against A-549 cells, compounds 8j and 8e showed exceptional potency against HCT-116 cells, compounds 8f and 8j demonstrated high efficacy against PANC-1 cells and compound 8h displayed remarkable potency against HaLa cells. The findings highlight the potential of these pyrimidinyl benzamide derivatives as targeted anticancer agents.