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Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-05 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01906 Valeria Famiglini 1 , Giuseppe La Regina 1 , Antonio Coluccia 1 , Domiziana Masci 1 , Andrea Brancale 2 , Roger Badia 3 , Eva Riveira-Muñoz 3 , José A. Esté 3 , Emmanuele Crespan 4 , Alessandro Brambilla 4 , Giovanni Maga 4 , Myriam Catalano 5, 6 , Cristina Limatola 5, 6 , Francesca Romana Formica 7 , Roberto Cirilli 7 , Ettore Novellino 8 , Romano Silvestri 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-05 00:00:00 , DOI: 10.1021/acs.jmedchem.6b01906 Valeria Famiglini 1 , Giuseppe La Regina 1 , Antonio Coluccia 1 , Domiziana Masci 1 , Andrea Brancale 2 , Roger Badia 3 , Eva Riveira-Muñoz 3 , José A. Esté 3 , Emmanuele Crespan 4 , Alessandro Brambilla 4 , Giovanni Maga 4 , Myriam Catalano 5, 6 , Cristina Limatola 5, 6 , Francesca Romana Formica 7 , Roberto Cirilli 7 , Ettore Novellino 8 , Romano Silvestri 1
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We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8–37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N–Y181C HIV-1 strains. Six racemic mixtures, 8, 23–25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.
中文翻译：
手性吲哚基芳砜非核苷逆转录酶抑制剂作为新型有效和广谱抗HIV-1药物
我们设计并合成了一系列手性吲哚基芳砜（IAS）作为新的HIV-1 NNRTI。新的IAS 8 – 37显示出对HIV-1 WT NL4-3菌株和K103N，Y181C，Y188L和K103N-Y181C突变HIV-1菌株的有效抑制。六个外消旋混合物，8，23 - 25，31，和33，在半制备级被分离成其纯对映体。带有手性（α-甲基苄基）的（R）-8对映体优于（S）-对应物。带有（S）丙氨酸单元（S）-23的IAS衍生物，（S，R）-25，（S）-31和（S）-33比相应的（R）-对映异构体显着更有效。化合物23保护海马神经元细胞免受兴奋性毒性损伤，而依非韦伦（EFV）不能与谷氨酸的神经毒性作用形成对比。目前的结果突出了手性IASs作为新的NNRTIs，具有对突变HIV-1菌株的改善的抗药性并降低了神经毒性作用。
更新日期：2017-07-05
中文翻译：
手性吲哚基芳砜非核苷逆转录酶抑制剂作为新型有效和广谱抗HIV-1药物
我们设计并合成了一系列手性吲哚基芳砜（IAS）作为新的HIV-1 NNRTI。新的IAS 8 – 37显示出对HIV-1 WT NL4-3菌株和K103N，Y181C，Y188L和K103N-Y181C突变HIV-1菌株的有效抑制。六个外消旋混合物，8，23 - 25，31，和33，在半制备级被分离成其纯对映体。带有手性（α-甲基苄基）的（R）-8对映体优于（S）-对应物。带有（S）丙氨酸单元（S）-23的IAS衍生物，（S，R）-25，（S）-31和（S）-33比相应的（R）-对映异构体显着更有效。化合物23保护海马神经元细胞免受兴奋性毒性损伤，而依非韦伦（EFV）不能与谷氨酸的神经毒性作用形成对比。目前的结果突出了手性IASs作为新的NNRTIs，具有对突变HIV-1菌株的改善的抗药性并降低了神经毒性作用。
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