Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.

Antonella Messore,Luigi Scipione,Sandro Cosconati,Valentina Noemi Madia,Enzo Tramontano,Valeria Tudino,Nicole Grandi,Roberta Costi,Ettore Novellino,Angela Corona,Francesca Esposito,Daniela De Vita,Davide Ialongo,Mathieu Métifiot,Marie-Line Andreola,Giorgio Amendola,Francesco Saccoliti,Roberto Di Santo,Alessandro De Leo

doi:10.1021/acs.jmedchem.1c00535

Abstract

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg2+ titration experiments demonstrated that our compounds coordinate the Mg2+ cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme.

Highlights

The human immunodeficiency virus type 1 (HIV-1) is the agent responsible for the acquired immunodeficiency syndrome (AIDS)
The synthesis of compounds 4j,l−t and 5j,l−t was performed as reported in Scheme 2
The synthetic pathway starts with an O-alkylation of diethyl 2-(((4-hydroxyphenyl)amino)methylene)malonate[50] (9) with the appropriate alkyl halide to obtain intermediates 10a−j

Summary

■ INTRODUCTION

The human immunodeficiency virus type 1 (HIV-1) is the agent responsible for the acquired immunodeficiency syndrome (AIDS). This trend of activity could be ascribable to the coexistence of the carboxylic acid function in the 3-position, along with substituents characterized by both moderate degrees of freedom and steric hindrance in the 6position of the quinolinonyl ring (a benzyloxybenzyl group in the case of derivative 4t and a biphenylmethyl moiety for derivative 4s) Within this subseries, 7 derivatives (4m,o,r−t and 5l,o) out of 18 tested showed high inhibitory activities, with IC50 values lower than 10 μM, 5 compounds (4n,q and 5m,p,r) proved to be active with 10 μM < IC50 < 30, and only 6 ethers (4l,p and 5n,q,s,t) reported inhibitory activity with IC50 values >30 μM.

11 RALh EFVi

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES