Design, synthesis, molecular docking and biological evaluation of novel pyrazole derivatives bearing quinoxalinone moiety as multi-targeted anticancer agents

•A series of pyrazole derivatives bearing quinoxalinone were designed and synthesized.•Cytotoxicity was evaluated against MCF-7, HCT-116 and A549 cell lines.•Compounds 4e and 4 h exhibited promising inhibitory activity against TS enzyme, BRaf and EGFR kinases.•The anticancer activity results were validated with molecular docking simulation study with the TS protein.•In silico pharmacokinetics properties for drug likeness of compounds were determined. Based on a multitarget-directed drug design technique, a series of new quinoxalinone-based pyrazole derivatives (4a-h) were designed and synthesized. The potency of newly synthesized molecules to inhibit the antiproliferation of the human cancer cell lines MCF-7 (breast), HCT-116 (colon), and A549 (lung) was examined. The most effective compounds against the examined cancer cell lines were 4e, 4f, 4 g, and 4 h. Among these, compounds 4e and 4 h had a strong anticancer activity that was equivalent to sorafenib. The capacity of the potent compounds (4e, 4f, 4 g, and 4 h) to inhibit the in vitro activity of the thymidylate synthase (TS) enzyme, BRaf, and EGFR kinases was also tested. With IC50 values for the TS enzyme, BRaf kinase, and EGFR kinase ranging from 1.16 to 2.97 μM, 1.28 to 3.69 μM, and 1.93 to 4.28 μM, respectively, all the investigated compounds showed a noticeable inhibitory action. Among the synthesized hybrids, compound 4 h showed IC50 value of 2.04, 2.69 and 1.93 μM against MCF-7, HCT-116, and A549 cell line, respectively, and 1.16, 1.28 and 1.93 nM against TS, BRaf and EGFR kinase enzyme, respectively. All of the synthesized hybrids adhered to Lipinski's guidelines, which suggested that they would have favorable oral drug-like qualities. To determine the probable interaction between the potent compounds and the TS active site, molecular docking study was conducted. [Display omitted]