New nicotinamide–thiadiazol hybrids as VEGFR-2 inhibitors for breast cancer therapy: design, synthesis and <i>in silico</i> and <i>in vitro</i> evaluation
Walid E. Elgammal, Hazem Elkady, Reda G. Yousef, Wagdy M. Eldehna, Dalal Z. Husein, Fatma G. Amin, Bshra A. Alsfouk, Eslam B. Elkaeed, Ibrahim H. Eissa, Ahmed M. Metwaly
Abstract
mechanistic studies further confirmed the activation of the intrinsic apoptotic pathway, as evidenced by caspase-3 activation (8.2-fold), Bax upregulation (6.9-fold), and Bcl-2 downregulation (3.68-fold). Computational studies, including molecular docking and 200 ns molecular dynamics (MD) simulations, confirmed the stable interaction of 7a with VEGFR-2, showing binding affinities comparable to sorafenib. Further validation through MM-GBSA, ProLIF, PCAT, and FEL analyses reinforced its strong binding capability. Additionally, ADMET predictions suggested favorable pharmacokinetic properties, including good absorption, high plasma protein binding, and non-CYP2D6 inhibition. Moreover, toxicity analysis classified 7a as non-mutagenic and non-carcinogenic, with a lower predicted toxicity than sorafenib. Finally, density functional theory (DFT) calculations highlighted the structural stability and reactivity of 7a, further supporting its potential as a VEGFR-2 inhibitor. These findings suggest that 7a is a promising VEGFR-2 inhibitor with significant anticancer potential, favorable pharmacokinetics, and an improved safety profile. Further preclinical studies and structural modifications are warranted to optimize its therapeutic potential.