2. Academic Validation
  3. Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents

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

  • J Med Chem. 2017 Aug 10;60(15):6528-6547. 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
Affiliations

Affiliations

  • 1 Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 2 Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, U.K.
  • 3 AIDS Research Institute-IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autonóma de Barcelona , 08916 Badalona, Spain.
  • 4 Institute of Molecular Genetics IGM-CNR, National Research Council , Via Abbiategrasso 207, I-27100 Pavia, Italy.
  • 5 Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Dipartimento di Fisiologia e Farmacologia "Vittorio Erspamer", Sapienza Università di Roma , Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 6 IRCCS Neuromed , Via Atinense 18, I-86077 Pozzilli, Italy.
  • 7 Dipartimento del Farmaco, Istituto Superiore di Sanità , Viale Regina Elena 299, I-00161 Roma, Italy.
  • 8 Dipartimento di Farmacia, Università di Napoli Federico II , Via Domenico Montesano 49, I-80131 Napoli, Italy.
PMID: 28628334 DOI: 10.1021/acs.jmedchem.6b01906
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.

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