Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.,Acta Pharmaceutica Sinica B

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Improving the positional adaptability: structure-based design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.
Acta Pharmaceutica Sinica B ( IF 14.7 ) Pub Date : 2019-10-17 , DOI: 10.1016/j.apsb.2019.09.007
Kaijun Jin _{1,

2} , Minjie Liu _{1,

2} , Chunlin Zhuang _{1,

2} , Erik De Clercq ₃ , Christophe Pannecouque ₃ , Ge Meng _{1,

2} , Fener Chen _{1,

2}

Affiliation

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.

中文翻译：

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。

为了提高我们之前报道的萘基二芳基三嗪 (NP-DATAs) 的位置适应性，我们提出了一系列新型联苯取代的二芳基三嗪 (BP-DATAs) 的合成，这些化合物在 C-6 位上具有柔性侧链。这些化合物对野生型 (WT) HIV-1 表现出优异的效力，EC50 值范围为 2.6 至 39 nmol/L，其中大多数对一组 HIV-1 突变株表现出低纳摩尔抗病毒效力。化合物 5j 和 6k 对 WT、单和双 HIV-1 突变体和逆转录酶 (RT) 具有最佳活性，可与两种参考药物（EFV 和 ETR）和我们的先导化合物 NP-DATA (1) 相媲美。分子模型显示，DATA 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。还讨论了初步的构效关系和PK曲线。

更新日期：2019-10-17

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