Novel Thiazolidine-2,4-Dione Derivatives as Potential VEGFR-2 Inhibitors: Synthesis, Biological Testing, and in Silico Studies

In this work novel 2,4-dioxothiazolidine-derived compounds targeting VEGFR-2 were designed and synthesized. Such compounds were evaluated for their anti-proliferative and VEGFR-2 inhibitory abilities. Compound 17 specifically demonstrated the strongest anti-proliferative activity against the HCT-116 cell line, with an IC50 value of 10.09 mu M. Additionally, compounds 15, 18, and 19 revealed good anti-proliferative effects with IC50 values of 12.46, 16.87, and 12.35 mu M, respectively. Compound 17 demonstrated potent anti-VEGFR-2 efficacy, with an IC50 value of 0.068 mu M, which was comparable to sorafenib (IC50 value of 0.058 mu M). Compound 17 induced apoptosis in HCT-116 cancer cells and caused G0-G1 phase cell cycle arrest. Furthermore, it upregulated BAX levels (5.1-fold) and downregulated Bcl-2 levels (4.2-fold), indicating its pro-apoptotic effects. Compound 17 also increased caspase-8 and caspase-9 levels by 3.3-fold and 4.7-fold, respectively, compared to the control. The computational studies provided insights into the kinetic, structural properties, and binding mode of the VEGFR-2-17 complex. The DFT calculations elucidated compound 17 ' s structural and electronic properties, while computational ADMET and toxicity tests suggested acceptable degrees of drug-likeness potential for the synthesized compounds. Our findings suggest that compound 17 holds promise as a potent apoptotic VEGFR-2 inhibitor and may guide future efforts in developing new anticancer drugs.