2. Academic Validation
  3. New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

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

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: giuseppe.laregina@uniroma1.it.
  • 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: romano.silvestri@icloud.com.
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.

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