10.1021/acs.jmedchem.6b01906.s002 Valeria Famiglini Valeria Famiglini Giuseppe La Regina Giuseppe La Regina Antonio Coluccia Antonio Coluccia Domiziana Masci Domiziana Masci Andrea Brancale Andrea Brancale Roger Badia Roger Badia Eva Riveira-Muñoz Eva Riveira-Muñoz José A. Esté José A. Esté Emmanuele Crespan Emmanuele Crespan Alessandro Brambilla Alessandro Brambilla Giovanni Maga Giovanni Maga Myriam Catalano Myriam Catalano Cristina Limatola Cristina Limatola Francesca Romana Formica Francesca Romana Formica Roberto Cirilli Roberto Cirilli Ettore Novellino Ettore Novellino Romano Silvestri Romano Silvestri Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV‑1 Agents American Chemical Society 2017 racemic mixtures chiral indolyarylsulfones NNRTI semipreparative level EFV alanine unit excitotoxic insult K 103N HIV Chiral Indolylarylsulfone Non-Nucleoside WT NL 4-3 strain Transcriptase Inhibitors enantiomer resistance profile chiral IASs Compound 23 IAS derivatives New Potent K 103N Y 181C Y 188L 2017-06-19 00:00:00 Dataset https://acs.figshare.com/articles/dataset/Chiral_Indolylarylsulfone_Non-Nucleoside_Reverse_Transcriptase_Inhibitors_as_New_Potent_and_Broad_Spectrum_Anti-HIV_1_Agents/5173387 We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs <b>8</b>–<b>37</b> 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, <b>8</b>, <b>23</b>–<b>25</b>, <b>31</b>, and <b>33</b>, were separated at semipreparative level into their pure enantiomers. The (<i>R</i>)-<b>8</b> enantiomer bearing the chiral (α-methylbenzyl) was superior to the (<i>S</i>)-counterpart. IAS derivatives bearing the (<i>S</i>) alanine unit, (<i>S</i>)-<b>23</b>, (<i>S</i>,<i>R</i>)-<b>25</b>, (<i>S</i>)-<b>31</b>, and (<i>S</i>)-<b>33</b>, were remarkably more potent than the corresponding (<i>R</i>)-enantiomers. Compound <b>23</b> 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.