Benzimidazole-Linked-۱,۳,۴-Thiadiazol-۲-Amine Derivatives: Computational Screening, Synthesis, and Biological Evaluation as Potential VEGFR-۲ Inhibitors

VEGFR-۲ expression and its activation are upregulated, causing angiogenesis. This process is significant and critical for tumor development, progression, and metastasis. As a consequence, VEGFR-۲ has become the center of attention for cancer treatment scientists because the inhibition of VEGFR-۲ kinases has become essential in the field of oncological research with the ultimate goal of stopping angiogenesis and terminating the development of malignant tumors. In this study, the target molecule inhibitors were developed via the synthesis of Benzimidazole-۱,۳,۴-thiadiazol-۲-amine derivatives. Out of ۳۰ screened molecules, AP۳, AP۵, AP۱۰, AP۱۲, AP۱۶, AP۱۷, AP۱۸, AP۲۰, AP۲۴, and AP۲۹ which possess most drug-likeness properties are considered as the most potent and either selected for wet lab synthesis. VEGFR-۲ kinase assay was performed at a test concentration of ۱۰ μM. Compounds AP۱۷ and AP۲۹ are at top of the list due to their excellent inhibition activities of the VEGFR۲ kinase (IC۵۰ values are ۱.۸۶ µM and ۳.۸۴ µM, respectively), and compared to pazopanib (the IC۵۰ value is ۰.۰۹۲ µM), they displayed this activity quite well. The activity of the synthesized compounds were determined in ۵ cancerous cell lines (breast-MCF-۷, MDA-MB-۲۳۱, kidney-HEK-۲۹۳, and lung-A۵۴۹) with sulforhodamine B (SRB) assay. Based on the trial, the compound AP۱۷ displayed the best potency against A-۵۴۹ with a GI۵۰ value of ۵.۳۵ μM, more so than against HEK-۲۹۳ and MCF-۷ cells with a GI۵۰ value of ۷.۲۰ and ۸.۹۰ μM, respectively. The fact that only this particular compound demonstrated medium cytotoxicity against the MDA-MB-۲۳۱ (GI۵۰ =۱۸.۸۹ μM) reflects the popularity and preference of this compound. As a consequence of the current examination, we have concluded that the inhibitors possess good potential of VEGFR۲ kinase for future use.

کلیدواژه ها:

ADMET ، Molecular docking ، Anticancer ، VEGFR-۲ ، Synthesis