Novel Thiazolidine‐2,4‐Dione Derivatives as Potential VEGFR‐2 Inhibitors: Synthesis, Biological Testing, and <i>in Silico</i> Studies

Abstract

Abstract 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 IC 50 value of 10.09 μM. Additionally, compounds 15 , 18 , and 19 revealed good anti‐proliferative effects with IC 50 values of 12.46, 16.87, and 12.35 μM, respectively. Compound 17 demonstrated potent anti‐VEGFR‐2 efficacy, with an IC 50 value of 0.068 μM, which was comparable to sorafenib (IC 50 value of 0.058 μM). 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.