Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach

Eur J Med Chem. 2014 Jun 10:80:112-21. doi: 10.1016/j.ejmech.2014.04.036. Epub 2014 Apr 13.

Abstract

Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 μM (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail.

Keywords: Anti-HIV activities; DAPY; HIV-1; HIV-2; Molecular modeling; Structure–activity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • HIV-1 / physiology
  • Molecular Docking Simulation
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • pyrimidine