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

Affiliation

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.

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