2. Academic Validation
  3. Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

Indolylarylsulfones carrying a heterocyclic tail as very potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors

  • J Med Chem. 2014 Dec 11;57(23):9945-57. doi: 10.1021/jm5011622.
Valeria Famiglini 1,  Giuseppe La Regina,  Antonio Coluccia,  Sveva Pelliccia,  Andrea Brancale,  Giovanni Maga,  Emmanuele Crespan,  Roger Badia,  Eva Riveira-Muñoz,  José A Esté,  Rosella Ferretti,  Roberto Cirilli,  Claudio Zamperini,  Maurizio Botta,  Dominique Schols,  Vittorio Limongelli,  Bruno Agostino,  Ettore Novellino,  Romano Silvestri
Affiliations

Affiliation

  • 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.
PMID: 25418038 DOI: 10.1021/jm5011622
Abstract

We synthesized new indolylarylsulfone (IAS) derivatives carrying a heterocyclic tail at the indole-2-carboxamide nitrogen as potential anti-HIV/AIDS agents. Several new IASs yielded EC50 values <1.0 nM against HIV-1 WT and mutant strains in MT-4 cells. The (R)-11 enantiomer proved to be exceptionally potent against the whole viral panel; in the Reverse Transcriptase (RT) screening assay, it was remarkably superior to NVP and EFV and comparable to ETV. The binding poses were consistent with the one previously described for the IAS non-nucleoside Reverse Transcriptase inhibitors. Docking studies showed that the methyl group of (R)-11 points toward the cleft created by the K103N mutation, different from the corresponding group of (S)-11. By calculating the solvent-accessible surface, we observed that the exposed area of RT in complex with (S)-11 was larger than the area of the (R)-11 complex. Compounds 6 and 16 and enantiomer (R)-11 represent novel robust lead compounds of the IAS class.

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