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

• Main Authors: Angela Corona, Valentina Onnis, Claudia Del Vecchio, Francesca Esposito, Yung-Chi Cheng, Enzo Tramontano
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Molecules
• Subjects: hiv-1 therapeutic agents; rt dual inhibitors; hiv-1 ribonuclease h; nicotinic acid esters; nicotinic acid amide
• Online Access: https://www.mdpi.com/1420-3049/25/6/1338

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, <b>21</b>, inhibited RNase H function with an IC₅₀ of 14 &#181;M and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound <b>21</b> 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 <b>21</b> as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.