Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety

Abstract

Background: Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity. Objective: In this study, we have designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2-yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines and selectivity against NIH/3T3 mouse embryonic fibroblast cell lines. Cholinesterase inhibition effects of these compounds were also measured to investigate the relationship between anticancer activity and cholinesterases. Method: The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measuring proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used for measuring apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages. Results: Compounds 2e, 2f, and 2k have been established as the most active antitumor agents with selective cytotoxicities (76.58±6.43, 55.13±5.75, and 32.94±3.02 µM respectively for A549; 86.48±3.60, 97.12±30.21, and 59.29±3.95 µM respectively for C6), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines. Conclusion: The results have shown that compounds 2e, 2f, and 2k have potential anticancer agents against A549 and C6 cell lines.