Design, synthesis, apoptotic antiproliferative, and antioxidant activities of a new series of 2-mercaptobenzimidazole/3-cyanopyridin-2-one hybrids as dual EGFR/BRAFV600E inhibitors

A novel series of 2-mercaptobenzimidazole-based 3-cyanopyridin-2-one hybrids (7a-l) was designed and synthesized as potential dual inhibitors of EGFR and BRAF^V600E kinases. The antiproliferative activity was evaluated against four human Cancer cell lines (MCF-7, A-549, HT-29, and Panc-1) and a normal epithelial cell line (MCF-10A). Compound 7c exhibited the highest potency (GI₅₀ = 6 μM) and was comparably effective to the reference doxorubicin (GI₅₀ = 5 μM) against the four Cancer cell lines analyzed. Compound 7c also showed potent EGFR (IC₅₀ = 0.12 μM) and BRAF^V600E (IC₅₀ = 0.05 μM) inhibition, induced Apoptosis via Caspase-3/8/9 activation, modulated Bax/Bcl-2 expression, and demonstrated strong antioxidant activity. Molecular docking, molecular dynamics (MD) simulations, and DFT analyses revealed key pharmacophoric interactions within the ATP-binding sites of EGFR and BRAF^V600E kinases, while in silico ADME predictions supported drug-likeness and showed no PAINS/Brenk structural alerts; however, these predictions do not establish safety, and experimental toxicology will be required. These findings identify compound 7c as a promising dual-target lead candidate for further optimization in Anticancer drug development.

Apoptosis; BRAF(V600E); Benzimidazole; Cyanopyridine; DFT; EGFR; cancer.