Novel pyrazole–oxadiazole–chalcone/oxime hybrids as dual EGFR/VEGFR-2 inhibitors with promising anticancer potential: a comprehensive cytotoxicity evaluation, mechanistic insights and SAR analysis

A novel series of pyrazole-1,3,4-oxadiazole hybrids incorporating chalcone/oxime scaffolds (10a-10c, 11a-11c, 12a-12i, 13a-13i, and 14a-14i) was synthesized and subjected to an detailed cytotoxicity profile against the NCI-60 human cancer cell line panel. Several derivatives demonstrated broad-spectrum growth inhibition, with compounds 10b, 11a, and 11b emerging as the most active candidates, exhibiting mean GI₅₀ values in the low micromolar range (4.36-16.4 µM). A deeper biological assessment revealed that these hybrids act as dual inhibitors of EGFR and VEGFR-2, with compound 11b showing the highest potency (IC₅₀ = 26.38 nM and 114.17 nM, respectively). Mechanistic studies further confirmed that 11b induced G2/M phase arrest and triggered apoptotic pathways in MCF-7 cells. The oxime-containing analogs exhibited enhanced nitric oxide (NO) release, a property associated with modulation of angiogenesis and increased susceptibility of cancer cells to apoptosis, contributing to their observed anticancer activity. Molecular docking and structure-activity relationship analysis clarified the binding interactions and substitution patterns governing activity, and both cytotoxicity and mechanistic analyses converged on compound 11b as the most promising lead of the series.