Discovery of 2,4,6-trisubstituted pyrimidine derivatives as novel potent HIV-1 NNRTIs by exploiting the tolerant region II of the NNIBP

Eur J Med Chem. 2024 Nov 5:277:116708. doi: 10.1016/j.ejmech.2024.116708. Epub 2024 Jul 27.

Abstract

The rapid emergence of drug resistance severely reduces the clinical response of human immunodeficiency virus-1 (HIV-1) to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Herein, a series of 2,4,6-trisubstituted pyrimidine derivatives was designed and synthesized, with the aim to identify novel anti-HIV-1 agents with improved drug resistance profiles. The antiviral activity results demonstrated that all compounds showed excellent potency to wild-type (WT) HIV-1 strain (EC50 = 3.61-15.5 nM). Moreover, 13c was proved to be the most potent inhibitor against the whole tested viral panel, with EC50 ranging from 4.68 to 229 nM. In addition, 13c yielded moderate HIV-1 RT inhibition with IC50 value of 0.231 μM, which demonstrated it was a classical NNRTI. Molecular docking was further conducted to illustrate its binding mode with HIV-1 RT. These encouraging results indicated that 13c can be used as a lead compound for further study.

Keywords: 2,4,6-Trisubstituted pyrimidine derivatives; DAPYs; Drug resistance; HIV-1; NNRTIs.

MeSH terms

  • Anti-HIV Agents* / chemical synthesis
  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • HIV Reverse Transcriptase* / antagonists & inhibitors
  • HIV Reverse Transcriptase* / metabolism
  • HIV-1* / drug effects
  • HIV-1* / enzymology
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Docking Simulation*
  • Molecular Structure
  • Pyrimidines* / chemical synthesis
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Reverse Transcriptase Inhibitors* / chemical synthesis
  • Reverse Transcriptase Inhibitors* / chemistry
  • Reverse Transcriptase Inhibitors* / pharmacology
  • Structure-Activity Relationship

Substances

  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Anti-HIV Agents
  • HIV Reverse Transcriptase
  • pyrimidine
  • reverse transcriptase, Human immunodeficiency virus 1