Laboratory for Drug Design and Synthesis, Department of Pharmaceutical Chemistry, Indo-Soviet Friendship College of Pharmacy, Moga 142 001, Punjab, India.
Bioorg Med Chem. 2011 Sep 15;19(18):5569-76. doi: 10.1016/j.bmc.2011.07.039. Epub 2011 Jul 26.
A series of forty two N-(1,3-diaryl-3-oxopropyl)amides were synthesized via an efficient, modified Dakin-West reaction and were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have been presented. Selected active xanthine oxidase inhibitors (3r, 3s, and 3zh) were assessed in vivo to study their anti-hyperuricemic effect in potassium oxonate induced hyperuricemic mice model. Compound 3s emerged as the most potent xanthine oxidase inhibitor (IC(50)=2.45 μM) as well as the most potent anti-hyperuricemic agent. The basis of significant inhibition of xanthine oxidase by 3s was rationalized by its molecular docking into catalytic site of xanthine oxidase.
通过高效、改良的 Dakin-West 反应合成了一系列 42 种 N-(1,3-二芳基-3-氧代丙基)酰胺，并首次对其体外黄嘌呤氧化酶抑制活性进行了评价。提出了构效关系分析。选择具有活性的黄嘌呤氧化酶抑制剂（3r、3s 和 3zh）进行体内评估，以研究它们在氧嗪酸钾诱导的高尿酸血症小鼠模型中的抗高尿酸血症作用。化合物 3s 表现出最强的黄嘌呤氧化酶抑制活性（IC50=2.45 μM）和最强的抗高尿酸血症作用。3s 对黄嘌呤氧化酶的显著抑制作用是通过其分子对接进入黄嘌呤氧化酶的催化位点来合理化的。
