Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors.
Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors.
复制标题
DOI：
10.1016/j.ejmech.2014.05.059
复制
发表时间：
2014-07
影响因子：
6.7
通讯作者：
Ge Meng;Yang Liu;A. Zheng;Fener Chen;Wen‐xue Chen;E. De Clercq;C. Pannecouque;J. Balzarini
中科院分区：
文献类型：
--
作者：
Ge Meng;Yang Liu;A. Zheng;Fener Chen;Wen‐xue Chen;E. De Clercq;C. Pannecouque;J. Balzarini
本文报道了一系列新的非核苷类逆转录酶抑制剂（NNRTIs）的设计、合成和抗病毒评价。这些目标分子的基本骨架是二芳基嘧啶，在嘧啶支架和芳基翼之间有一个取代的氨基。所有的新化合物都通过光谱分析进行了表征。以FDA批准的药物为对照，对整个靶分子进行体外抗hiv活性评价。大部分菌株对野生型（WT） HIV-1具有较强的抑菌活性，ic50值在0.0175 ~ 69.21 μM之间。2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)嘧啶（1d）对WT HIV-1具有较强的抗HIV-1活性，其选择性指数（SI）为106367，ic50值为1.75 nM，比AZT低47倍。化合物1对HIV-1双突变株（K103N/Y181C）和HIV-2的ic50值分别为5.33 μM和5.05 μM，具有广谱抑制活性。初步探讨了其构效关系（SAR）。我们还讨论了野生型和突变型与HIV-1 RT的结合模式。
This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for theirin vitroanti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50values in the range of 0.0175–69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50value of 1.75 nM, which was 47 fold lower than that of AZT. Compound1dalso showed a broad-spectrum inhibitory activity, with an IC50value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure–activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed.