Synthesis and biological evaluation of new imidazole, pyrimidine, and purine derivatives and analogs as inhibitors of xanthine oxidase.
Synthesis and biological evaluation of new imidazole, pyrimidine, and purine derivatives and analogs as inhibitors of xanthine oxidase.
复制标题
作为黄嘌呤氧化酶抑制剂的新型咪唑、嘧啶和嘌呤衍生物及类似物的合成和生物学评价。
DOI：
10.1021/jm950876u
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发表时间：
1996
影响因子：
7.3
通讯作者：
V. Scartoni
中科院分区：
文献类型：
--
作者：
G. Biagi;A. Costantini;L. Costantino;I. Giorgi;O. Livi;P. Pecorari;M. Rinaldi;V. Scartoni
合成了4，5-二取代的咪唑、2，4，5-三取代的嘧啶、2-取代的嘌呤、噻唑并[3，2-α]嘌呤、[1，3]噻嗪并[3，2-α]嘌呤、噻唑并[2，3-i]嘌呤、[1，3]噻嗪并-[2，3-i]嘌呤和6-取代的吡唑并[3，4-d]嘧啶的几种衍生物，并作为黄嘌呤氧化酶的抑制剂进行了测试。其中，一些4-（酰氨基）-5-氨基甲酰基咪唑和2-硫代烷基取代的嘌呤表现出非常好的抑制活性，比别嘌呤醇有效至少500倍。6-N-烷基吡唑并[3，4-d]嘧啶的无效性可归因于烷基链，其可根据抑制剂别嘌呤醇的结合的已知机制阻碍与钼的配位;咪唑衍生物的有效性，与4，5-二氨基-2-（硫代烷基）-6-羟基嘧啶，表明五元环在与酶的相互作用中的相对重要性。此外，角环化的[1，3]噻嗪并[2，3-i]嘌呤酮，这构成了一个有趣的新的一类抑制剂，与线性环化衍生物的弱活性一起，使我们能够更精确地表征面向底物次黄嘌呤的N（1）-C（2）位置的酶的亲脂性区域。
Several derivatives of 4,5-disubstituted imidazole, 2,4,5-trisubstituted pyrimidine, 2-substituted purine, thiazolo[3,2-alpha]purine, [1,3]thiazino[3,2-alpha]purine, thiazolo[2,3-i]purine, [1,3]thiazino-[2,3-i]purine, and 6-substituted pyrazolo[3,4-d]pyrimidine were synthesized and tested as inhibitors of the xanthine oxidase enzyme. Of those, some 4-(acylamino)-5-carbamoylimidazoles and 2-thioalkyl-substituted purines exhibited very good inhibitory activity, being at least 500 times more effective than allopurinol. The ineffectiveness of 6-n-alkylpyrazolo[3,4-d]pyrimidines is imputable to the alkyl chain which could hinder the coordination with molybdenum according to the known mechanism for the binding of the inhibitor allopurinol; the effectiveness of imidazole derivatives, by contrast with the ineffectiveness of 4,5-diamino-2-(thioalkyl)-6-hydroxypyrimidines, indicates the relative importance of the five-membered ring in the interaction with the enzyme. Moreover, the marked effectiveness of the angularly-cyclized [1,3]thiazino[2,3-i]purinones, which constitute an interesting new class of inhibitors, together with the weak activity of linearly-cyclized derivatives, allowed us to characterize more precisely the lipophilic region of the enzyme facing the N(1)-C(2) positions of the substrate hypoxanthine.