Design, Synthesis, and Biological Evaluation of Novel Dihydropyrimidinone Derivatives as Potential Anticancer Agents and Tubulin Polymerization Inhibitors.

Abstract

The severity and prevalence of cancer in modern time are a huge global health burden. Continuous efforts are being made toward the development of newer therapeutic candidates to treat and manage this ailment. The dihydropyrimidinone scaffold is one of the key nuclei that have been highly explored and investigated against cancer. It has the potential to combat the consequences of cancer by interacting with several biological targets. Tubulin polymerization inhibition is one such strategy to prevent the progression of cancer. In the presented work, we have synthesized a series of sixteen dihydropyrimidinone derivatives by following a rational drug design. The synthesized compounds have been characterized by ¹H NMR and ¹³C NMR and were further evaluated for cytotoxic activity against breast cancer cell lines (MCF-7 and MDA-MB-231), lung cancer cell lines (A549), and colon cancer cell lines (HCT-116). Compounds 5D and 5P were found most potent and revealed a better cytotoxic activity compared with the standard drug colchicine. Furthermore, the tubulin polymerization inhibition assay revealed that compound 5D showed better inhibition than colchicines, whereas compound 5P revealed an almost equal inhibition to that of colchicine. Furthermore, to investigate the possible mode of action and binding patterns, compounds 5P and 5D were subjected to molecular docking against tubulin (Protein Data Bank ID: ISA0). The results showed that compounds revealed significant interactions and were well occupied inside the cavity of tubulin. The compounds 5D and 5P may serve as new leads in drug development against cancer.