Dihydro-alkylthio-benzyl-oxopyrimidines as inhibitors of reverse transcriptase:: Synthesis and rationalization of the biological data on both wild-type enzyme and relevant clinical mutants
Dihydro-alkylthio-benzyl-oxopyrimidines as inhibitors of reverse transcriptase:: Synthesis and rationalization of the biological data on both wild-type enzyme and relevant clinical mutants
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DOI：
10.1021/jm0708230
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发表时间：
2007-12-27
影响因子：
7.3
通讯作者：
Botta, Maurizio
中科院分区：
文献类型：
--
作者：
Mugnaini, Claudia;Alongi, Maddalena;Botta, Maurizio
通过平行合成的方法合成了一系列新的S-DABO类似物，它们在杂环的2、5和6位具有不同的取代模式，并被评价为人类免疫缺陷病毒1型（HIV-1）的抑制剂。大多数化合物在酶和细胞实验中都被证明对野生型酶具有高活性，其中一种化合物是迄今为止报道的最活跃的逆转录酶抑制剂（EC50wt = 25 pM）。通过分子模拟方法深入研究了化合物对临床相关突变菌株的效力普遍丧失，从而证明非核苷结合口袋的入口动态可以代表分子抑制活性的基础。
A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.