Abstract

Angiogenesis, the formation of new blood vessels, plays an important role in tumor growth and metastasis. Vascular endothelial growth factor receptor-2 (VEGFR-2) is a key regulator of this process and a crucial target for anti-angiogenic cancer therapies. In this work, a series of pyrazole–pyrazoline derivatives were designed by incorporating various heterocyclic moieties, such as thiazole, benzothiazole, pyridine, furan, thiophene, and pyrrole, to improve VEGFR-2 inhibition. Using an in silico approach, molecular docking studies with AutoDock Vina revealed strong binding interactions, particularly hydrophobic and hydrogen bonding, with amino acid residues of the VEGFR-2 protein. The compounds were tested for pharmacokinetic properties and drug-likeness using SwissADME, and their absorption, distribution, metabolism, excretion, and toxicity profiles were predicted through the pkCSM tool. Among the tested compounds, C-64 emerged as the most promising lead candidate, showing optimum binding affinity, compliance with Lipinski’s and Veber’s rules, and no predicted hepatotoxicity, cardiotoxicity, or mutagenicity. Moreover, C-64 displayed a high LD50 value, suggesting low toxicity, and the lowest total clearance, indicating prolonged retention. It also aligned well with key physicochemical parameters in the bioavailability radar and was positioned in the white region of the BOILED-Egg model, suggesting efficient gastrointestinal absorption. These findings position C-64 as a promising candidate for further optimization and preclinical development in cancer therapy.

Key words: Pyrazole, pyrazoline, molecular docking, VEGFR-2, ADMET