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

Reda G Yousef; Ibrahim H Eissa; Hazem Elkady; Wagdy M Eldehna; Ahmed B M Mehany; Ahmed Nabeeh; Ibrahim M Ibrahim; Alaa Elwan; Mohamed Ayman El-Zahabi

doi:10.1080/07391102.2023.2294170

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

J Biomol Struct Dyn. 2023 Dec 15:1-18. doi: 10.1080/07391102.2023.2294170. Online ahead of print.

Authors

Reda G Yousef¹, Ibrahim H Eissa¹, Hazem Elkady¹, Wagdy M Eldehna², Ahmed B M Mehany³, Ahmed Nabeeh⁴, Ibrahim M Ibrahim⁵, Alaa Elwan¹, Mohamed Ayman El-Zahabi¹

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
³ Zoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo, Egypt.
⁴ Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
⁵ Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt.

PMID: 38100580
DOI: 10.1080/07391102.2023.2294170

Abstract

Herin, new nicotinamide candidates were designed and synthesized as VEGFR-2 inhibitors. In vitro antiproliferative activities were assessed against MCF-7, HepG-2 and HCT-116 cancer cell lines. The top cytotoxic members 15a, 15b, 16, 18a, and 18b were estimated against their selected target (VEGFR-2). Further mechanistic tests were studied for the most potent cytotoxic candidate 18a, these studies revealed the ability of compound 18a to hinder the progression of HCT-116 cells at S and Pre-G1phases besides boosting early and late apoptosis. Also compound 18a 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 18a-VEGFR-2 complex indicated the high steadiness of compound 18a in the VEGFR-2 active site. This study presents compound 18a as a lead candidate that can be optimized to get a strong VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.

Keywords: MD simulation; Nicotinamides; VEGFR-2; anticancer; apoptosis; docking studies.