Novel indolylarylsulfone derivatives as covalent HIV-1 reverse transcriptase inhibitors specifically targeting the drug-resistant mutant Y181C

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are widely used in combination therapies against HIV-1. However, emergent and transmitted drug resistance compromise their efficacy in the clinical setting. Y181C is selected in patients receiving nevirapine, etravirine and rilpivirine, and together with K103N is the most prevalent NNRTI-associated mutation in HIVinfected patients. Herein, we report on the design, synthesis and biological evaluation of a novel series of indolylarylsulfones bearing acrylamide or ethylene sulfonamide reactive groups as warheads to inactivate Cys181-containing HIV-1 RT via a Michael addition reaction. Compounds I-7 and I-9 demonstrated higher selectivity towards the Y181C mutant than against the wild-type RT, in nucleotide incorporation inhibition assays. The larger size of the NNRTI binding pocket in the mutant enzyme facilitates a better fit for the active compounds, while stacking interactions with Phe227 and Pro236 contribute to inhibitor binding. Mass spectrometry data were consistent with the covalent modification of the RT, although off-target reactivity constitutes a major limitation for further development of the described inhibitors.

An Overview on Indole Aryl Sulfide/Sulfone (IAS) as Anti‐HIV Non‐Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

“…In this direction, several studies have been carried out for the design and synthesis of indole derivatives with CÀ S bonds for the evaluation of their medicinal importance. [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] In 2003, Silvestri et al [52] reported indolylarylsulfones, a nonnucleoside reverse transcriptase inhibitors (NNRTIs) as a potent anti-HIV-1 carrying NNRTI resistance mutations for the first time. The NNRTIs based anti-HIV agent have received significant attention due to their favorable pharmacokinetics properties and low toxicity.…”

“…These results suggest the valuable idea for the design of new series of IAS NNRTIs with reduced neurotoxic effects and improved resistance profile against the mutant HIV-1 strains. [66][67][68][69]…”

Recent Advances on the Role of Nitrogen‐Based Heterocyclic Scaffolds in Targeting HIV through Reverse Transcriptase Inhibition

“…Also, stacking interactions with Phe227 and Pro236 amino acids is responsible for effective interaction. [71] Pribut and team reported several benzimidazolones hybrids against HIV strains. In the presence of clinically significant resistance strains, such as K103N and Y181C, compounds are nevertheless effective against HIV-1.…”

“…Larger binding pocket of NNRTI in the mutant enzyme is probably responsible for appreciable interaction of compounds 12 and 13 (Figure 7). Also, stacking interactions with Phe227 and Pro236 amino acids is responsible for effective interaction [71] …”

Covalently Targeted Highly Conserved Tyr318 to Improve the Drug Resistance Profiles of HIV-1 NNRTIs: A Proof-of-Concept Study

“…Furthermore, Y181 is the most easily mutated amino acid in NNIBP, and a variety of mutant strains have been reported, including Y181C, Y181V and Y181I. These reported RT covalent inhibitors showed excellent activity against wild-type HIV-1 strain, but greatly reduced activity against mutant strains [ 8 , 9 , 10 ]. Therefore, covalent inhibitors targeting conserved amino acids were proposed to improve the anti-drug resistance in this work.…”