Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents

Valeria Famiglini, Giuseppe La Regina, Antonio Coluccia, Domiziana Masci, Andrea Brancale, Roger Badia, Eva Riveira-Muñoz, José A. Esté, Emmanuele Crespan, Alessandro Brambilla, Giovanni Maga, Myriam Catalano, Cristina Limatola, Francesca Romana Formica, Roberto Cirilli, Ettore Novellino, Romano Silvestri

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Abstract

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.

Original languageEnglish
Pages (from-to)6528-6547
Number of pages20
JournalJournal of Medicinal Chemistry
Volume60
Issue number15
DOIs
Publication statusPublished - Aug 10 2017

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Famiglini, V., La Regina, G., Coluccia, A., Masci, D., Brancale, A., Badia, R., Riveira-Muñoz, E., Esté, J. A., Crespan, E., Brambilla, A., Maga, G., Catalano, M., Limatola, C., Formica, F. R., Cirilli, R., Novellino, E., & Silvestri, R. (2017). Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents. Journal of Medicinal Chemistry, 60(15), 6528-6547. https://doi.org/10.1021/acs.jmedchem.6b01906