N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase
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- 作者：Luca Pescatori ; Mathieu M茅tifiot ; Suhman Chung ; Takashi Masoaka ; Giuliana Cuzzucoli Crucitti ; Antonella Messore ; Giovanni Pupo ; Valentina Noemi Madia ; Francesco Saccoliti ; Luigi Scipione ; Silvano Tortorella ; Francesco Saverio Di Leva ; Sandro Cosconati ; Luciana Marinelli ; Ettore Novellino ; Stuart F. J. Le Grice ; Yves Pommier ; Christophe Marchand ; Roberta Costi ; Roberto Di Santo
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4610-4623
- 全文大小：456K
- ISSN：1520-4804
文摘
Bifunctional quinolinonyl DKA derivatives were first described as nonselective inhibitors of 3鈥?processing (3鈥?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 渭M. 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.