Innovative Nicotinamide‐Dihydrothiadiazole Compounds for Targeting VEGFR‐2: Design, Synthesis, and Mechanistic Exploration in Breast Cancer Treatment

Abstract In this study, a series of nicotinamide‐dihydrothiadiazole hybrids were synthesized and evaluated for their anticancer potential through VEGFR‐2 inhibition. Among the synthesized compounds, 7c demonstrated a very promising VEGFR‐2 inhibitory activity (IC₅₀ = 0.098 ± 0.05 µM), comparable to the reference drug sorafenib (IC₅₀ = 0.1 ± 0.05 µM). In vitro cytotoxicity studies revealed that 7c exhibited significant anticancer activity against MDA‐MB‐231 (IC₅₀ = 6.92 ± 0.4 µM) and MCF‐7 (IC₅₀ = 9.18 ± 0.7 µM) breast cancer cell lines, with minimal toxicity toward normal cells (WI‐38 and WISH). Mechanistic studies indicated that 7c induces G0/G1 phase arrest and apoptosis, as evidenced by increased late apoptotic populations (45.58%) and upregulation of caspase‐3, Bax, and a significant reduction in Bcl‐2. Computational analyses, encompassing molecular docking and 200 ns molecular dynamics (MD) simulations, demonstrated the stable interaction of 7c with VEGFR‐2, highlighting its excellent binding affinity. Additionally, Swiss ADMET predictions highlighted the favorable pharmacokinetic and safety profiles of 7c , including non‐mutagenic and noncarcinogenic properties, moderate absorption, and high plasma protein binding (>90%). These findings establish nicotinamid‐dihydrothiadiazole hybrids, particularly 7c , as promising VEGFR‐2 inhibitors with dual mechanisms of angiogenesis inhibition and apoptosis induction.