Zafar Humaira, Iqbal Sarosh, Javaid Sumaira, Khan Khalid M, Choudhary Muhammad I
H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
Department of Applied Chemistry, Govt. College University, Faisalabad, Faislabad-38000, Pakistan.
Med Chem. 2018;14(5):524-535. doi: 10.2174/1573406413666171129224919.
Xanthine oxidase is an important enzyme which catalyzes the production of uric acid and superoxide anion from xanthine. The over-production of these products leads to different disease conditions. For instance, uric acid is responsible for hyperuricemia, gout, and arthritis, while superoxide anion contributes to the oxidative stress, and related diseases. Hence XO is an important pharmacological target for the treatment of a range of diseases.
Based on the structural resemblance of pyrimidines with xanthine, a series of previously synthesized ethyl 6- methyl-2-oxo-1, 2, 3, 4-tetrahydro-5-pyrimidinecarboxylate derivatives were evaluated for XO inhibitory activity.
Among 25 pyrimidone derivatives, 22 were found to be good to weak inhibitors with IC50 values in the range of 14.4 - 418 µM. Compounds 3, 14, 15, 18, and 21-23 were significant inhibitors, and thus analyzed for their kinetic parameters. Among them compounds 14, 15, 18, and 23 were competitive, 21 and 22 showed non-competitive, while 23 was a mixed-type of inhibitor. Molecular docking studies highlighted the interactions of these inhibitors with critical amino acids of XO, such as Val1011, Phe649, Lys771, and others. Moreover, the cytotoxicity studies on these selected inhibitors showed all these compounds to be non-cytotoxic.
These non-cytotoxic, significant XO inhibitors can thus be further investigated for the treatment of hyperuricemia, and gout.
黄嘌呤氧化酶是一种重要的酶，它催化黄嘌呤生成尿酸和超氧阴离子。这些产物的过量产生会导致不同的疾病状况。例如，尿酸会导致高尿酸血症、痛风和关节炎，而超氧阴离子会导致氧化应激及相关疾病。因此，黄嘌呤氧化酶是治疗一系列疾病的重要药理学靶点。
基于嘧啶与黄嘌呤的结构相似性，对一系列先前合成的6-甲基-2-氧代-1,2,3,4-四氢-5-嘧啶羧酸乙酯衍生物进行了黄嘌呤氧化酶抑制活性评估。
在25种嘧啶酮衍生物中，发现22种为良好至弱抑制剂，IC50值在14.4 - 418 µM范围内。化合物3、14、15、18和21 - 23是显著抑制剂，因此对其动力学参数进行了分析。其中化合物14、15、18和23为竞争性抑制剂，21和22表现为非竞争性抑制剂，而23为混合型抑制剂。分子对接研究突出了这些抑制剂与黄嘌呤氧化酶关键氨基酸（如Val1011、Phe649、Lys771等）的相互作用。此外，对这些选定抑制剂的细胞毒性研究表明所有这些化合物均无细胞毒性。
因此，这些无细胞毒性的显著黄嘌呤氧化酶抑制剂可进一步用于高尿酸血症和痛风的治疗研究。
