N-Substituted Quinolinonyl Diketo Acid Derivatives as HIV Integrase Strand Transfer Inhibitors and Their Activity against RNase H Function of Reverse Transcriptase

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.

The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity

“…They act against multiple viral enzymes that include reverse transcriptase, integrase and ribonuclease. These agents bind in the active site of integrase, ribonuclease and reverse transcriptase with the help of magnesium ion with acidic residues in their catalytic site and in that way they halt the function of these enzymes [63,64,65,66,67]. These quinolonyl diketo acid analogues are synthesized by introduction of various alkylating group at the nitrogen atom of the quinolinone ring [63].…”

“…These agents bind in the active site of integrase, ribonuclease and reverse transcriptase with the help of magnesium ion with acidic residues in their catalytic site and in that way they halt the function of these enzymes [63,64,65,66,67]. These quinolonyl diketo acid analogues are synthesized by introduction of various alkylating group at the nitrogen atom of the quinolinone ring [63]. Similarly the mono and bifunctional quinolinonyl diketo acids are also potent inhibitors of strand transfer function of HIV integrase, which are synthesized by treating aniline with ethyl orthoformate and ethyl acetoacetate [65,66,67].…”

Crystal structure of ethyl (E)-3-(cyclopropylamino)-2-(2,4-dichloro-5-fluorobenzoyl) acrylate, C15H14Cl2FNO3

“…Since the introduction of the first quinolone as a therapeutic agent of urinary tract infections [6], quinolones have become one of the main drugs to treat bacterial infections, widely used in the treatment of diseases including sexually transmitted diseases, urinary tract infections, chronic bronchitis, community acquired pneumonia, respiratory infections and so on [7]. Among these, the most notable ones are 4-quinolones [8][9][10][11][12], which form the core backbone of several quinolone-based and commerciallyavailable antibiotics. For these reasons, it is necessary to develop simple and efficient approaches for the synthesis of 4-quinolones.…”

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

“…Later, N -substituted quinolinonyl DKA derivatives were reported as IN and RT RNase H in inhibitors [ 139 ]. These analogs provided an opportunity to investigate the role of the arylmethyl group linked to quinolonyl nitrogen.…”

“…Several of these analogs were found to be potent dual INIs showing high activity against the ST and RNase H function. Compound 39 (4-[1-(2,4-difluorophenyl)methyl-4(1 H )-quinolinon-3-yl]-2-hydroxy-4-oxo-2-butenoic acid) displayed the highest ST activity with IC 50 value of 10 nM and RNase H activity with an IC 50 value of approximately 36 μM [ 139 ].…”