In situ click chemistry-based discovery of 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs by exploiting the tolerant region I in binding pocket

Bioorg Med Chem. 2023 Dec 15:96:117484. doi: 10.1016/j.bmc.2023.117484. Epub 2023 Sep 23.

Abstract

HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC50 = 0.01-0.26 μM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket.

Keywords: Click chemistry; DAPY; HIV-1; In situ screening; NNRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / pharmacology
  • Click Chemistry
  • Drug Design
  • HIV Reverse Transcriptase
  • HIV-1*
  • Heterocyclic Compounds, 1-Ring
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Reverse Transcriptase Inhibitors
  • Triazoles
  • Anti-HIV Agents
  • HIV Reverse Transcriptase
  • Heterocyclic Compounds, 1-Ring