1. N‑substituted quinolinonyl diketo acid derivatives as HIV integrase strand transfer inhibitors and their activity against RNase H function of reverse transcriptase
- Author
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Takashi Masoaka, Antonella Messore, Giuliana Cuzzucoli Crucitti, Valentina Noemi Madia, Ettore Novellino, Sandro Cosconati, Francesco Saverio Di Leva, Silvano Tortorella, Luca Pescatori, Christophe Marchand, Suhman Chung, Stuart F.J. Le Grice, Yves Pommier, Luciana Marinelli, Giovanni Pupo, Francesco Saccoliti, Mathieu Métifiot, Luigi Scipione, Roberto Di Santo, Roberta Costi, Pescatori, L, Métifiot, M, Chung, S, Masoaka, T, Cuzzucoli Crucitti, G, Messore, A, Pupo, G, Madia, Vn, Saccoliti, F, Scipione, L, Tortorella, S, Di Leva, F, Cosconati, Sandro, Marinelli, L, Novellino, E, Le Grice, Sf, Pommier, Y, Marchand, C, Costi, R, Di Santo, R., Pescatori, Luca, Métifiot, Mathieu, Chung, Suhman, Masoaka, Takashi, Cuzzucoli Crucitti, Giuliana, Messore, Antonella, Pupo, Giovanni, Madia, Valentina Noemi, Saccoliti, Francesco, Scipione, Luigi, Tortorella, Silvano, Di Leva, Francesco Saverio, Marinelli, Luciana, Novellino, Ettore, Le Grice, Stuart F. J., Pommier, Yve, Marchand, Christophe, Costi, Roberta, and Di Santo, Roberto
- Subjects
Models, Molecular ,Stereochemistry ,Ribonuclease H ,HIV Infections ,HIV Integrase ,Quinolones ,Virus Replication ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,Catalytic Domain ,Drug Discovery ,Humans ,HIV Integrase Inhibitors ,Bifunctional ,RNase H ,IC50 ,biology ,Molecular Structure ,RNA-Directed DNA Polymerase ,Keto Acids ,In vitro ,Reverse transcriptase ,Integrase ,HIV, Integrase, Ribonuclease H, Antiviral Drugs, Medicinal Chemistry ,chemistry ,biology.protein ,Benzyl group ,HIV-1 ,Molecular Medicine ,Selectivity ,HeLa Cells ,immunodeficiency virus type 1 ,ribonuclease H ,dual inhibitors ,biological evaluation ,in vitro ,DNA ,design ,site ,hydroxytropolones ,raltegravir - Abstract
Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3′-processing (3′-P) and strand transfer (ST) functions of HIV-1 integrase (IN), while 7-aminosubstituted quinolinonyl derivatives were proven IN strand transfer inhibitors (INSTIs) that also displayed activity against ribonuclease H (RNase H). In this study, we describe the design, synthesis, and biological evaluation of new quinolinonyl diketo acid (DKA) derivatives characterized by variously substituted alkylating groups on the nitrogen atom of the quinolinone ring. Removal of the second DKA branch of bifunctional DKAs, and the amino group in position 7 of quinolinone ring combined with a fine-tuning of the substituents on the benzyl group in position 1 of the quinolinone, increased selectivity for IN ST activity. In vitro, the most potent compound was 11j (IC50 = 10 nM), while the most active compounds against HIV infected cells were ester derivatives 10j and 10l. In general, the activity against RNase H was negligible, with only a few compounds active at concentrations higher than 10 μM. The binding mode of the most potent IN inhibitor 11j within the IN catalytic core domain (CCD) is described as well as its binding mode within the RNase H catalytic site to rationalize its selectivity. (Chemical Presented).
- Published
- 2015