Basic quinolinonyl diketo acid derivatives as inhibitors of HIV integrase and their activity against RNase H function of reverse transcriptase

  • J Med Chem. 2014 Apr 24;57(8):3223-34. doi: 10.1021/jm5001503.
Roberta Costi  1 ,  Mathieu Métifiot ,  Suhman Chung ,  Giuliana Cuzzucoli Crucitti ,  Kasthuraiah Maddali ,  Luca Pescatori ,  Antonella Messore ,  Valentina Noemi Madia ,  Giovanni Pupo ,  Luigi Scipione ,  Silvano Tortorella ,  Francesco Saverio Di Leva ,  Sandro Cosconati ,  Luciana Marinelli ,  Ettore Novellino ,  Stuart F J Le Grice ,  Angela Corona ,  Yves Pommier ,  Christophe Marchand ,  Roberto Di Santo
Affiliations
  • 1. Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma , P.le Aldo Moro 5, I-00185 Roma, Italy.
PMID: 24684270 DOI: 10.1021/jm5001503
Abstract

A series of Antiviral basic quinolinonyl diketo acid derivatives were developed as inhibitors of HIV-1 IN. Compounds 12d,f,i inhibited HIV-1 IN with IC50 values below 100 nM for strand transfer and showed a 2 order of magnitude selectivity over 3'-processing. These strand transfer selective inhibitors also inhibited HIV-1 RNase H with low micromolar potencies. Molecular modeling studies based on both the HIV-1 IN and RNase H catalytic core domains provided new structural insights for the future development of these compounds as dual HIV-1 IN and RNase H inhibitors.