The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.

中文翻译：

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2-(芳基氨基)-6-(三氟甲基)烟酸衍生物：对病毒复制具有活性的新型 HIV-1 RT 双重抑制剂


艾滋病流行的持续存在以及所需的终生治疗表明对新型 HIV-1 抑制剂的持续需求。在这种情况下，HIV-1 逆转录酶 (RT) 相关核糖核酸酶 H (RNase H) 功能是一个有前途的药物靶点。在这里，我们报告了一系列在 2-氨基-6-(三氟甲基)烟酸支架上开发的化合物，作为有前景的 RNase H 双重抑制剂进行研究。在 44 种测试的化合物中，有 34 种在低微摩尔范围内抑制 HIV-1 RT 相关的 RNase H 功能，其中 7 种在基于细胞的检测中也显示出抑制病毒复制的作用，选择性指数高达 10。最有前途的化合物, 21，在基于细胞的检测中抑制 RNase H 功能，IC50 为 14 µM，并抑制 HIV-1 复制，选择性指数大于 10。作用模式研究表明，化合物 21 是一种变构双位点化合物，抑制 HIV- 1 RT 功能，在存在对非核苷抑制剂具有抗性的循环变体携带的突变的情况下也阻断聚合酶功能，并且 RNase H 功能与 RNase H 结构域内的保守区域相互作用。证明化合物 21 是设计新型变构 RNase H 抑制剂的有前途的先导材料，该抑制剂可有效对抗病毒复制，且不具有显着的细胞毒性作用。