Specific targeting of highly conserved residues in the HIV-1 reverse transcriptase primer grip region. 2. Stereoselective interaction to overcome the effects of drug resistant mutations

  • J Med Chem. 2009 Feb 26;52(4):1224-8. doi: 10.1021/jm801395v.
Stefania Butini  1 ,  Margherita Brindisi ,  Sandro Cosconati ,  Luciana Marinelli ,  Giuseppe Borrelli ,  Salvatore Sanna Coccone ,  Anna Ramunno ,  Giuseppe Campiani ,  Ettore Novellino ,  Samantha Zanoli ,  Alberta Samuele ,  Gianluca Giorgi ,  Alberto Bergamini ,  Michela Di Mattia ,  Silvana Lalli ,  Bruno Galletti ,  Sandra Gemma ,  Giovanni Maga
Affiliations
  • 1. Dipartimento Farmaco Chimico Tecnologico, Universita di Siena, via Aldo Moro 2, 53100 Siena, Italy.
PMID: 19170521 DOI: 10.1021/jm801395v
Abstract

Starting from the prototypic compound 4, we describe new, potent, and broad-spectrum pyrrolobenzo(pyrido)oxazepinones antivirals. A biochemical and enzymological investigation was performed for defining their mechanism of inhibition at either recombinant HIV-1 RT wild type and non-nucleoside Reverse Transcriptase inhibitors (NNRTIs)-resistant mutants. For the novel compounds (S)-(+)-5 and (S)-(-)-7, a clear-cut stereoselective mechanism of enzyme inhibition was found. Molecular modeling studies were performed for revealing the underpinnings of this behavior.