New tolfenamic acid derivatives with hydrazine-1-carbothioamide and 1,3,4-oxadiazole moieties targeting VEGFR: synthesis, in silico studies, and in vitro anticancer assessment

VEGFR-2 is required for tumor angiogenesis and metastasis. As a cancer therapeutic strategy, blocking VEGFR-2 signaling pathway has gained much interest. Our work aimed to design and synthesize two series of new tolfenamic acid (TA) derivatives containing hydrazine-1-carbothioamide (compounds 4A-E) or 1,3,4-oxadiazole (compounds 5A-E) as possible VEGFR-2 tyrosine kinase inhibitors. The designed compounds were successfully synthesized using conventional organic chemical methods. Docking studies were performed to learn how the newly synthesized compounds bind to VEGFR-2 tyrosine kinase. The new compounds were evaluated in vitro for their cytotoxic activity against three human cancer cell lines. Cell cycle progression and induction of apoptosis by flow cytometry and immunoblotting were investigated. Molecular modeling showed that compounds 4A, 4B, 4C, 5A, and 5B have high docking score (ΔG) in the active pocket of the molecular target VEGFR-2. The new TA derivatives also showed good pharmacokinetic characteristics. Compound 4B, the most potent cytotoxic TA derivative, was found to have an EC 50 value comparable to that of sorafenib against VEGFR-2, causing cell cycle arrest at the G2/M phase and induction of the extrinsic and endoplasmic reticulum apoptosis pathways. In summary, compound 4B has the potential to be an antagonist of VEGFR-2, which is overexpressed in solid tumors.