New nicotinamide derivatives as potential anticancer agents targeting VEGFR-2: design, synthesis, <i>in vitro</i> , and <i>in silico</i> studies

Abstract

Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors. <i>In vitro</i> antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 cancer cell lines. The top cytotoxic members <b>15a</b>, <b>15b</b>, <b>16, 18a</b>, and <b>18b</b> were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate <b>18a</b>, these studies revealed the ability of compound <b>18a</b> to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late apoptosis. Also compound <b>18a</b> was found to significantly decrease the levels immunomodulatory proteins TNF-α and IL-6 while showing a four-fold rise in an apoptotic marker caspase-3 when compared to control cells. The therapeutic index of the designed derivatives was evaluated by computational ADMET and toxicity calculations as well as their potentiality to occupy the VEGFR-2 active site was signposted by molecular docking assessments. Finally, molecular dynamic simulation studies of compound <b>18a</b>-VEGFR-2 complex indicated the high steadiness of compound <b>18a</b> in the VEGFR-2 active site. This study presents compound <b>18a</b> as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.