Design, synthesis and biological evaluation of benzamide derivatives as novel anticancer agents.

Gastric cancer remains one of the most prevalent and lethal malignancies worldwide, underscoring the urgent need for novel therapeutic strategies. In this study, we designed and synthesized 21 benzamide derivatives to explore their broad-spectrum anticancer potential. During biological evaluation, BJ-13 exhibited relatively potent antiproliferative activity across multiple cancer cell lines, with notably strong effects observed in gastric cancer cells. Mechanistic studies demonstrated that BJ-13 induced significant intracellular reactive oxygen species (ROS) accumulation, leading to mitochondrial membrane potential collapse and caspase-dependent apoptosis. Western blot analysis confirmed the modulation of key apoptotic proteins, including upregulation of Bax and Cleaved Caspase-3 and downregulation of Bcl-2. These findings suggest that BJ-13 exerts its anticancer effects primarily through ROS-mediated mitochondrial dysfunction and activation of apoptotic pathways. In addition, we performed in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions for all derivatives. The results indicated that these compounds, including BJ-13, possess favorable pharmacokinetic and safety profiles, supporting their potential as drug-like candidates. In conclusion, BJ-13 represents a promising anticancer agent with a novel mechanism involving oxidative stress-induced apoptosis, providing a strong foundation for further preclinical investigation.