Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors
复制标题
提高位置适应性：基于结构的联苯取代二芳基三嗪作为新型非核苷 HIV-1 逆转录酶抑制剂的设计
DOI：
10.1016/j.apsb.2019.09.007
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发表时间：
2020-02-01
影响因子：
14.5
通讯作者：
Chen, Fener
中科院分区：
文献类型：
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作者：
Jin, Kaijun;Liu, Minjie;Chen, Fener
为了提高萘二芳基三嗪（NP-DATAs）的位置适应性，合成了一系列在C-6位上带有柔性侧链的联苯取代二芳基三嗪（BP-DATAs）。这些化合物对野生型（WT）HIV-1表现出优异的效力，EC 50值范围为2.6至39 nmol/L，其中大多数对一组HIV-1突变株显示出低纳摩尔的抗病毒效力。化合物5 j和6 k具有与两种参考药物（EFV和ETR）和我们的先导化合物NP-DATA（1）相当的针对WT、单和双HIV-1突变体和逆转录酶（RT）酶的最佳活性。分子模拟结果表明，DATAs的C-6位侧链占据了HIV-1逆转录酶非核苷结合口袋（NNIBP）的入口通道，从而提高了活性。初步构效关系和PK特征也进行了讨论。(C)2020中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines (NP-DATAs), synthesis of a series of novel biphenyl-substituted diaryltriazines (BP-DATAs) with a flexible side chain attached at the C-6 position is presented. These compounds exhibited excellent potency against wild-type (WT) HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant strains. Compounds 5j and 6k had the best activity against WT, single and double HIV-1 mutants and reverse transcriptase (RT) enzyme comparable to two reference drugs (EFV and ETR) and our lead compound NP-DATA (1). Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket (NNIBP) attributing to the improved activity. The preliminary structure-activity relationship and PK profiles were also discussed. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.