TY - JOUR
T1 - Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents
AU - Famiglini, Valeria
AU - La Regina, Giuseppe
AU - Coluccia, Antonio
AU - Masci, Domiziana
AU - Brancale, Andrea
AU - Badia, Roger
AU - Riveira-Muñoz, Eva
AU - Esté, José A.
AU - Crespan, Emmanuele
AU - Brambilla, Alessandro
AU - Maga, Giovanni
AU - Catalano, Myriam
AU - Limatola, Cristina
AU - Formica, Francesca Romana
AU - Cirilli, Roberto
AU - Novellino, Ettore
AU - Silvestri, Romano
PY - 2017/8/10
Y1 - 2017/8/10
N2 - © 2017 American Chemical Society. 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.
AB - © 2017 American Chemical Society. 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.
U2 - 10.1021/acs.jmedchem.6b01906
DO - 10.1021/acs.jmedchem.6b01906
M3 - Article
VL - 60
SP - 6528
EP - 6547
IS - 15
ER -
