Design, synthesis, and molecular dynamics-driven evaluation of quinoline-sulfonamide derivatives as potent and selective EGFR inhibitors with promising anti-cancer efficacy and safety profiles.

The creation of new molecules that target EGFR is essential for the progression of cancer treatment. This study synthesized and evaluated 16 quinoline-sulfonamide derivatives for their potential as anti-cancer agents. Compound 8c, which contains a methoxy group on the benzenesulfonamide tail, exhibited notable EGFR inhibitory activity (IC = 0.161 µM), similar to that of Erlotinib (IC = 0.142 µM). Compound 8c demonstrated enhanced in-vitro cytotoxicity against HCT-116, MCF-7, HeLa, and HepG2 cancer cell lines. Studies on the cell cycle and apoptosis demonstrated that compound 8c caused G1/S arrest and markedly enhanced apoptosis in HepG2 cells. In-vivo, compound 8c demonstrated comparable and/or superior efficacy compared to doxorubicin in decreasing tumor volume, weight, TNF-alpha, and COX-2 levels in the SEC model, alongside improved histopathological and immunohistochemical results. Molecular docking and dynamic simulations confirmed its stable binding to EGFR, exhibiting superior stability metrics in comparison to Erlotinib. Pharmacokinetic and toxicity evaluations indicated that compound 8c exhibits favorable drug-like properties and a safer toxicity profile. These findings identify compound 8c as a potential candidate for the development of safe and effective anti-cancer therapies, necessitating additional preclinical investigations.