Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs.,ACS Infectious Diseases

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Structure-Activity Relationship Exploration of NNIBP Tolerant Region I Leads to Potent HIV-1 NNRTIs.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-07-03 , DOI: 10.1021/acsinfecdis.0c00327
Dongwei Kang _{1,

2} , Yanying Sun ₁ , N Arul Murugan ₃ , Da Feng ₁ , Fenju Wei ₁ , Jing Li ₁ , Xiangyi Jiang ₁ , Erik De Clercq ₄ , Christophe Pannecouque ₄ , Peng Zhan _{1,

5} , Xinyong Liu _{1,

5}

Affiliation

Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound 1 (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series of novel diarylpyrimidines derivatives carrying a structurally diverse motif at the right wing of the lead K-5a2 was designed and synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded exceptionally potent activity against HIV-1 wild-type (50% effective concentration (EC₅₀) = 3.30 nM) and mutant strain RES056 (EC₅₀ = 22.6 nM) in MT-4 cells; in the reverse transcriptase inhibitory assay, 8a (half maximal inhibitory concentration (IC₅₀) = 0.028 μM) was remarkably superior to that of K-5a2 (IC₅₀ = 0.300 μM) and comparable to that of etravirine (ETR; IC₅₀ = 0.011 μM). Notably, 8a exhibited better druggability than that of K-5a2, including significantly reduced CYP enzymatic inhibitory activity (IC₅₀ > 50 μM), lower human ether-à-go-go related gene (hERG) inhibition (IC₅₀ > 30 μM), and improved metabolic stability (short half-life, T_1/2 = 77.5 min) in vitro.

中文翻译：

NNIBP耐受区I的结构-活性关系探索导致有效的HIV-1 NNRTI。

在我们实验室的先前努力已导致开发人类免疫缺陷病毒1型（HIV-1）非核苷逆转录酶抑制剂（NNRTI）噻吩[3,2- d ]嘧啶化合物1（K-5a2）野生型和突变型HIV-1菌株。在这项工作中，设计并合成了一系列新型的二芳基嘧啶衍生物，它们在前导K-5a2的右翼带有结构多样的基序，并被合成为潜在的抗HIV-1药物。结果表明8a对HIV-1野生型（50％有效浓度（EC ₅₀）= 3.30 nM）和突变菌株RES056（EC ₅₀= 22.6 nM）在MT-4细胞中；在逆转录酶抑制测定中，图8a（半数最大抑制浓度（IC ₅₀）= 0.028μM）是显着优于的K-5A2（IC ₅₀ = 0.300μM）和比得上依曲韦林（ETR; IC ₅₀ = 0.011 μM）。值得注意的是，8a具有比K-5a2更好的药物相容性，包括CYP酶抑制活性显着降低（IC ₅₀ > 50μM），更低的人类以太相关基因（hERG）抑制（IC ₅₀ > 30μM），并改善了体外的代谢稳定性（半衰期短，T _1/2 = 77.5分钟）。

更新日期：2020-08-14

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