In vitro and In silico Xanthine Oxidase Inhibitory Activities of 3-Aryl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one Derivatives

Background Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders. Objectives The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases. Methods In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds. Results Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC50 values between 33.688 to 362.173 mu M. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC50 = 39.904 +/- 0.21 mu M) and 17 (IC50 = 33.688 +/- 0.30 mu M) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line. Conclusion This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.