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Open AccessArticle

2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication

1
Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, 09042 Monserrato, Cagliari, Italy
2
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
3
Department of Pharmacology, Yale University Medical School, New Haven, CT 06520-8066, USA
4
Genetics and Biomedical Research Institute, National Research Council, 09042 Monserrato, Italy
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(6), 1338; https://doi.org/10.3390/molecules25061338
Received: 28 February 2020 / Revised: 11 March 2020 / Accepted: 12 March 2020 / Published: 15 March 2020
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects. View Full-Text
Keywords: HIV-1 therapeutic agents; RT dual inhibitors; HIV-1 ribonuclease H; nicotinic acid esters; nicotinic acid amide HIV-1 therapeutic agents; RT dual inhibitors; HIV-1 ribonuclease H; nicotinic acid esters; nicotinic acid amide
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Corona, A.; Onnis, V.; Del Vecchio, C.; Esposito, F.; Cheng, Y.-C.; Tramontano, E. 2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication. Molecules 2020, 25, 1338.

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