Biological and computational assessment of new synthesized nicotinamides as potential immunomodulatory VEGFR-2 inhibitors

As an extension to our preceding studies on nicotinamide derivatives as anticancer agents, new nicotinamidebased candidates were designed and synthesized as VEGFR-2 inhibitors. The in vitro cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines (MCF-7, HepG-2 and HCT-116). The IC50 values for compound 17 were 2.61 +/- 0.01, 3.20 +/- 0.02, and 2.46 +/- 0.01 mu M, respectively, compared to sorafenib (4.21 +/- 0.03, 3.40 +/- 0.02, and 5.30 +/- 0.04 mu M) against MCF-7, HePG-2, and HCT-116. This indicated that compound 17 possess double strength relative to sorafenib against both MCF-7 and HCT-116. Compound 17 was the most promising VEGFR-2 inhibitor with IC50 value of 0.34 mu M that was slightly better than that of sorafenib (0.38 mu M). Further studies displayed the ability of compound 17 to arrest the growth of HCT-116 cells at the Pre-G1 and S phases. Additionally, compound 17 induced a significant increase in the total apoptosis rate of HCT-116 cells from 1.82 % to 26.69 %. Moreover, it showed high selectivity indices against HCT-116, HepG2, and MCF-7 cancer cells. Furthermore, compound 17 showed potent inhibitory activities on TNF-alpha and IL-6 and showed a notable rise in caspase-3 level. In addition, the potentiality of the designed derivatives to bind with and inhibit the VEGFR-2 enzyme was indicated by molecular docking assessments. MD simulation studies revealed the stability of compound 17 in the active site of VEGFR-2 for 100 ns. Based on the previous findings, compound 17 appears to be a promising apoptotic VEGFR-2 inhibitor and could potentially direct future efforts towards the development of novel anticancer medications.