Biochemistry Research Laboratory, School of Life Sciences, Swami Ramanand Teerth Marathwada University, Nanded, India.
J Enzyme Inhib Med Chem. 2010 Oct;25(5):615-21. doi: 10.3109/14756360903389849.
Xanthine oxidase (XO) is responsible for the pathological condition called gout. Inhibition of XO activity by various pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine-4-one derivatives was assessed and compared with the standard inhibitor allopurinol. Out of 10 synthesized compounds, two compounds, viz. 3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3b) and 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3g) were found to have promising XO inhibitory activity of the same order as allopurinol. Both compounds and allopurinol inhibited competitively with comparable Ki (3b: 3.56 microg, 3g: 2.337 microg, allopurinol: 1.816 microg) and IC(50) (3b: 4.228 microg, 3g: 3.1 microg, allopurinol: 2.9 microg) values. The enzyme-ligand interaction was studied by molecular docking using Autodock in BioMed Cache V. 6.1 software. The results revealed a significant dock score for 3b (-84.976 kcal/mol) and 3g (-90.921 kcal/mol) compared with allopurinol (-55.01 kcal/mol). The physiochemical properties and toxicity of the compounds were determined in silico using online computational tools. Overall, in vitro and in silico study revealed 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3g) as a potential lead compound for the design and development of XO inhibitors.
黄嘌呤氧化酶（XO）是导致痛风等病理状况的罪魁祸首。评估了各种吡唑并[3,4-d]噻唑并[3,2-a]嘧啶-4-酮衍生物对 XO 活性的抑制作用，并与标准抑制剂别嘌醇进行了比较。在所合成的 10 种化合物中，两种化合物，即 3-氨基-6-(2-羟基苯基)-1H-吡唑并[3,4-d]噻唑并[3,2-a]嘧啶-4-酮（3b）和 3-氨基-6-(4-氯-2-羟基-5-甲基苯基)-1H-吡唑并[3,4-d]噻唑并[3,2-a]嘧啶-4-酮（3g）被发现具有与别嘌醇相当的有前途的 XO 抑制活性。这两种化合物和别嘌醇均以竞争性方式抑制，Ki 值相当（3b：3.56 μg，3g：2.337 μg，别嘌醇：1.816 μg），IC50 值（3b：4.228 μg，3g：3.1 μg，别嘌醇：2.9 μg）。使用 BioMed Cache V. 6.1 软件中的 Autodock 进行分子对接研究了酶-配体相互作用。结果表明，与别嘌醇（-55.01 kcal/mol）相比，3b（-84.976 kcal/mol）和 3g（-90.921 kcal/mol）的对接得分均显著降低。使用在线计算工具在计算机上确定了化合物的物理化学性质和毒性。总体而言，体外和计算机研究表明 3-氨基-6-(4-氯-2-羟基-5-甲基苯基)-1H-吡唑并[3,4-d]噻唑并[3,2-a]嘧啶-4-酮（3g）可能成为设计和开发 XO 抑制剂的潜在先导化合物。
