New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

  • Eur J Med Chem. 2014 Jun 10:80:101-11. doi: 10.1016/j.ejmech.2014.04.027.
Valeria Famiglini  1 ,  Giuseppe La Regina  2 ,  Antonio Coluccia  1 ,  Sveva Pelliccia  1 ,  Andrea Brancale  3 ,  Giovanni Maga  4 ,  Emmanuele Crespan  4 ,  Roger Badia  5 ,  Bonaventura Clotet  5 ,  José A Esté  5 ,  Roberto Cirilli  6 ,  Ettore Novellino  7 ,  Romano Silvestri  8
Affiliations
  • 1. Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
  • 2. Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: [email protected].
  • 3. Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
  • 4. Institute of Molecular Genetics IGM-CNR, National Research Council, via Abbiategrasso 207, I-27100 Pavia, Italy.
  • 5. AIDS Research Institute - IrsiCaixa, Hospitals Germans Trias i Pujol, Universitat Autonóma de Barcelona, 08916 Badalona, Spain.
  • 6. Istituto Superiore di Sanità, Dipartimento del Farmaco, Viale Regina Elena 299, I-00161 Roma, Italy.
  • 7. Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131, Napoli, Italy.
  • 8. Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy. Electronic address: [email protected].
PMID: 24769348 DOI: 10.1016/j.ejmech.2014.04.027
Abstract

New indolylarylsulfone HIV-1 NNRTIs were synthesized to evaluate unexplored substitutions of the benzyl/phenylethyl group linked at the indole-2-carboxamide. Against the NL4-3 HIV-1 WT strain, 17 out 20 compounds were superior to NVP and EFV. Several compounds inhibited the K103N HIV-1 mutant strain at nanomolar concentration and were superior to EFV. Some derivatives were superior to EFV against the Y181C and L100I HIV-1 mutant strains. Against the NL4-3 HIV-1 strain, the enantiomers 24 and 25 showed small differences of activity. In contrast, 24 turned out significantly more potent than 25 against the whole panel of mutant HIV-1 strains. The docking studies suggested that the difference in the observed inhibitory activities of 24 and 25 against the K03N mutation could be due to a kinetic rather than affinity differences.

Keywords
AIDS; HIV-1; Indolylarylsulfone; Nonnucleoside inhibitor; Reverse transcriptase.