Discovery of new thiazolidine-2,4-dione derivatives as potential VEGFR-2 inhibitors: In vitro and in silico studies

Abstract

In this study, a series of seven novel 2,4-dioxothiazolidine derivatives with potential anticancer and VEGFR-2 inhibiting abilities were designed and synthesized as VEGFR-2 inhibitors. The synthesized compounds were tested <i>in vitro</i> for their potential to inhibit VEGFR-2 and the growth of HepG2 and MCF-7 cancer cell lines. Among the compounds tested, compound <b>22</b> (IC₅₀ = 0.079 μM) demonstrated the highest <i>anti</i>-VEGFR-2 efficacy. Furthermore, it demonstrated significant anti-proliferative activities against HepG2 (IC₅₀ = 2.04 ± 0.06 μM) and MCF-7 (IC₅₀ = 1.21 ± 0.04 M). Additionally, compound <b>22</b> also increased the total apoptotic rate of the MCF-7 cancer cell lines with cell cycle arrest at S phase. As well, computational methods were applied to study the VEGFR-2-<b>22</b> complex at the molecular level. Molecular docking and molecular dynamics (MD) simulations were used to investigate the complex's structural and kinetic characteristics. The DFT calculations further revealed the structural and electronic properties of compound <b>22</b>. Finally, computational ADMET and toxicity tests were performed indicating the likeness of the proposed compounds to be drugs. The results suggest that compound <b>22</b> displays promise as an effective anticancer treatment and can serve as a model for future structural modifications and biological investigations in this field.