Li Xiao, Gao Ping, Huang Boshi, Zhou Zhongxia, Yu Zhao, Yuan Zheng, Liu Huiqing, Pannecouque Christophe, Daelemans Dirk, De Clercq Erik, Zhan Peng, Liu Xinyong
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Department of Pharmacology, Shandong University School of Medicine, Shandong University, 44 West Culture Road, 250012 Jinan, Shandong, PR China.
Eur J Med Chem. 2017 Jan 27;126:190-201. doi: 10.1016/j.ejmech.2016.10.009. Epub 2016 Oct 5.
To further explore the chemical space around the entrance channel of HIV-1 reverse transcriptase (RT), a series of novel indolylarylsulfones (IASs) bearing N-substituted piperidine at indole-2-carboxamide were identified as potent HIV NNRTIs by structure-guided scaffold morphing and fragment rearrangement. All the IASs exhibited moderate to excellent potency against wild-type HIV-1 with EC values ranging from 0.62 μM to 0.006 μM 8 (EC = 6 nM) and 18 (EC = 9 nM) were identified as the most potent compounds, which were more active than NVP and DLV, and reached the same order of EFV and ETV. Furthermore, most compounds maintained high activity agaist various single HIV-1 mutants (L100I, K103N, E138K, Y181C) as well as one double mutant (F227L/V106A) with EC values in low-micromolar to double-digit nanomolar concentration ranges. Especially, 8 displayed outstanding potency against L100I (EC = 17 nM with a 2.8-fold resistance ratio) and 18 was relatively more potent to E138K mutant (EC = 43 nM with a 4.7-fold resistance ratio). Preliminary SARs and molecular modeling studies were also discussed in detail, which may provide valuable insights for further optimization.
为了进一步探索人类免疫缺陷病毒1型逆转录酶（RT）入口通道周围的化学空间，通过结构导向的支架变形和片段重排，一系列在吲哚-2-甲酰胺处带有N-取代哌啶的新型吲哚芳基砜（IASs）被鉴定为有效的HIV非核苷类逆转录酶抑制剂。所有的IASs对野生型HIV-1均表现出中等至优异的活性，其半数有效浓度（EC）值范围为0.62 μM至0.006 μM，化合物8（EC = 6 nM）和18（EC = 9 nM）被鉴定为最有效的化合物，它们比奈韦拉平（NVP）和地拉韦啶（DLV）更具活性，与依非韦伦（EFV）和依曲韦林（ETV）处于同一活性水平。此外，大多数化合物对各种单一HIV-1突变体（L100I、K103N、E138K、Y181C）以及一个双突变体（F227L/V106A）保持高活性，其EC值在低微摩尔至两位数纳摩尔浓度范围内。特别是，化合物8对L100I表现出卓越的活性（EC = 17 nM，耐药比为2.8倍），化合物18对E138K突变体相对更具活性（EC = 43 nM，耐药比为4.7倍）。还详细讨论了初步的构效关系（SARs）和分子模拟研究，这可能为进一步优化提供有价值的见解。
