Design, synthesis, and molecular modeling of quinoline-linked diphenylpyrazoles as multitarget EGFR, VEGFR-2, and COX-2 inhibitors with anticancer, anti-inflammatory and apoptosis-inducing properties.

Abstract

The development of multitarget-directed ligands (MTDLs) has emerged as a promising strategy for simultaneously modulating oncogenic, angiogenic, and inflammatory pathways implicated in cancer progression. In this study, a new series of quinoline-diphenylpyrazole hybrids were rationally designed, synthesized, and biologically evaluated as potential EGFR/VEGFR-2/COX-2 inhibitors. The synthesized compounds exhibited variable in vitro cytotoxic effect, with compounds 7f and 7k identified as the most potent derivatives. Compound 7f demonstrated IC50 values of 9.63, 12.17, 7.06, and 8.53 μM, whereas 7k exhibited IC50 values of 15.95, 19.71, 13.96, and 10.23 μM against HeLa, PC-3, HCT-116, and MCF-7 cancer cell lines, respectively. In the enzymatic evaluation, compound 7f revealed potent EGFR, VEGFR-2, and COX-2 inhibitory activities, with IC50 values of 0.041, 0.052, and 0.027 μM, respectively, comparable to reference inhibitors. Mechanistic studies demonstrated that 7f induced marked G2/M cell cycle arrest and triggered apoptosis via activation of the intrinsic apoptotic pathway in HCT-116 cells, as evidenced by upregulation of BAX, Caspase-3, and Caspase-9 and downregulation of Bcl-2. Moreover, computational molecular docking and molecular dynamics analyses revealed favorable multitarget binding modes and stable predicted ligand-target interactions, further supporting the proposed hybrid design strategy.