Design, Synthesis, and Molecular Docking Studies of 5‐Bromoindole‐2‐Carboxylic Acid Hydrazone Derivatives: In Vitro Anticancer and VEGFR‐2 Inhibitory Effects

Abstract

AbstractA new set of 5‐bromoindole‐2‐carboxylic acid hydrazone derivatives were synthesized and studied as potential inhibitors of VEGFR‐2 tyrosine kinase (TK). Various physical (color, melting point, etc.) and spectroscopic (IR, 1H NMR, 13C NMR, and MS) methods were used to determine the structure of the novel 5‐bromoindole hydrazone derivatives. A molecular docking study revealed that 5‐bromo‐N′‐(4‐hydroxy or 4‐chloro or 4‐(dimethyl amino) benzylidene or furan‐2‐ylmethylene)‐1H‐indole‐2‐carbohydrazide derivatives had the best binding energies against the VEGFR TK domain. All of the newly synthesized compounds displayed adequate absorption levels and did not appear to inhibit cytochrome P450. Furthermore, they did not show in silico hepatotoxicity. The novel indole hydrazone derivatives inhibited cell proliferation (measured by the MTT assay) in three human cancer cell lines tested, with the 5‐bromo‐N′‐(4‐(dimethyl amino) benzylidene)‐1H‐indole‐2‐carbohydrazide derivative (5BDBIC) being the most potent against Hep G2 hepatocellular carcinoma cells (IC50=14.3 μM), and almost similar to that of the standard VEGFR TK inhibitor sorafenib (IC50=6.2 μM). Compound 5BDBIC inhibited VEGFR‐2 TK activity leading to cell cycle arrest at the G2/M phase, and induction of the intrinsic apoptosis pathway. In conclusion, compound 5BDBIC is a promising antitumor agent that targets the tyrosine kinase activity of VEGFR.