Some novel benzimidazole and benzoxazole methyl ester derivatives as BCL2 inhibitors and BAX activators: Synthesis, anticancer activity and in silico evaluation.

Discovering novel anticancer drugs with high efficacy and minimal toxicity is of great importance in anticancer drug research and development. Apoptosis is a critical regulatory mechanism in cancer progression mediated by BCL2 family proteins and BAX, which together play a key role in the regulation of programmed cell death. In this study, a series of some novel methyl 2-(substitutedphenyl)-1H-benzimidazole-5(6)-carboxylate (2a-2p) and methyl 2-(substitutedphenyl)-benzoxazole-5-carboxylate (3a-3p) derivatives were designed, synthesized, and evaluated for anticancer activity against LNCaP, HepG2, and A549 cell lines, together with their effects on BCL2 and BAX mRNA expression. Although the benzoxazole derivatives did not exhibit the desired activity against the tested cell lines, several benzimidazole derivatives showed notable anticancer effects. Notably, methyl 2-(4-tert-butylphenyl)-1H-benzimidazole-5(6)-carboxylate (2l) was found to be more potent than the reference drug across all tested cell lines. Moreover, methyl 2-(4-isopropylphenyl)-1H-benzimidazole-5(6)-carboxylate (2h) exhibited activity comparable to the reference drug against the LNCaP cell line, while demonstrating superior potency against the other two cell lines. The effects of these two compounds on the expression levels of BCL2 and BAX were found to be consistent with the in vitro cytotoxicity results. Furthermore, molecular docking studies revealed that their interactions with both proteins were consistent with the experimental findings. In addition, in silico ADMET predictions indicated favorable oral bioavailability and low toxicity risks. These findings underscore the critical role of the benzimidazole scaffold and the effects of para substituents, identifying compounds 2h and 2l as promising lead candidates for the development of selective anticancer agents.