Design, synthesis, and evaluation of novel thiadiazole derivatives as potent VEGFR-2 inhibitors: a comprehensive in vitro and in silico study

Objective: This study aims to investigate the potential of designed 2,3-dihydro-1,3,4-thiadiazole derivatives as anti-proliferative agents targeting VEGFR-2, utilizing a multidimensional approach combining in vitro and in silico analyses. Methods: The synthesized derivatives were evaluated for their inhibitory effects on MCF-7 and HepG2 cancer cell lines. Additionally, VEGFR-2 inhibition was assessed. Further investigations into the cellular mechanisms were conducted to elucidate the effects of 20b (N-(4-((E)-1-(((Z)-5-Acetyl-3-(p-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene)hydrazono) ethyl) phenyl) benzamide) on cell cycle arrest and apoptosis induction. Furthermore, computational investigations, including molecular docking, MD simulations, DFT calculations, MM-GBSA, PCAT, and ADMET predictions were conducted. Results: Compound 20b emerged as a standout candidate with significantly lower IC50 values of 0.05 μM and 0.14 μM for MCF-7 and HepG2 cell lines, respectively. It exhibited notable VEGFR-2 inhibition (0.024 μM), surpassing the efficacy of sorafenib (0.041 μM). Compound 20b demonstrated cancer-specific targeting potential with a high selectivity index in normal WI-38 cells (IC50 0.19 μM). Mechanistic studies revealed its ability to arrest the cell cycle of MCF-7 cells and induce apoptosis (total apoptosis 34.47%, early apoptosis 18.48%, and late apoptosis 15.99%), supported by upregulated caspase-8 (3.42-fold) and caspase-9 (5.44-fold) expression. Additionally, 20b arrested the cell cycle of MCF-7 cells at the %G0-G1 phase. Computational investigations provided insights into its molecular interactions with VEGFR-2, contributing to the rational design and understanding of its pharmacological profile. Conclusions: Compound 20b presents as a promising anti-proliferative agent targeting VEGFR-2. Also, this comprehensive investigation underscores the potential of 2,3-dihydro-1,3,4-thiadiazole derivatives as promising candidates for further development in anti-cancer research.