H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
Department of Chemistry, University of Karachi, Karachi, 75270, Pakistan.
Med Chem. 2023;19(4):384-392. doi: 10.2174/1573406418666220620124034.
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.
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.
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.
Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC values between 33.688 to 362.173μM. 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 (IC = 39.904 ± 0.21 μM) and 17 (IC = 33.688 ± 0.30 μM) 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.
This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.
高尿酸血症与多种疾病有关，如动脉粥样硬化、关节炎、肾结石等。黄嘌呤氧化酶（XO）是一种能催化黄嘌呤转化为尿酸的酶。因此，XO 是治疗高尿酸血症和相关疾病的主要治疗靶点。
本研究旨在基于喹唑啉衍生物发现 XO 抑制剂，有望用于治疗痛风和其他高尿酸血症相关疾病。
在本研究中，合成了 18 种喹唑啉衍生物 2-19，并评估了它们对黄嘌呤氧化酶（XO）的体外抑制活性。此外，对最活性化合物 5 和 17 进行了动力学研究和计算对接。用人胚成纤维细胞（BJ）测量活性化合物的细胞毒性。
化合物 4-6、8、10、13、15-17 和 19 对 XO 表现出活性，IC 值在 33.688 至 362.173μM 之间。结果表明，化合物 5 和 17 具有显著的黄嘌呤氧化酶抑制活性。动力学和分子对接研究表明，化合物 5（IC=39.904±0.21μM）和 17（IC=33.688±0.30μM）结合在 XO 的别构位点，表现出非竞争性抑制类型。分子对接研究还预测嘧啶环的 NH 基团与 XO 的 Ser344 残基结合。此外，所有活性化合物对人胚成纤维细胞（BJ）细胞系均无细胞毒性。
本研究鉴定了一系列喹唑啉类化合物作为黄嘌呤氧化酶抑制剂，具有进一步研究的潜力。
