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

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ID: 100548
2020
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Abstract
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, , inhibited RNase H function with an IC 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 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 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.
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corona20202arylamino6trifluoromethylnicotinicmolecules Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Angela Corona, Valentina Onnis, Claudia Del Vecchio, Francesca Esposito, Yung-Chi Cheng, Enzo Tramontano
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Journal molecules
Year 2020
DOI
E1338
URL
Keywords
hiv-1 ribonuclease h hiv-1 therapeutic agents rt dual inhibitors nicotinic acid amide nicotinic acid esters

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