Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 2: discovery of novel [1,2,4]Triazolo[1,5-a]pyrimidines using a structure-guided core-refining approach

Eur J Med Chem. 2014 Oct 6:85:293-303. doi: 10.1016/j.ejmech.2014.07.104. Epub 2014 Jul 30.

Abstract

Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel [1,2,4]triazolo[1,5-a]pyrimidine derivatives were rationally designed via structure-based core refining approach, synthesized through the readily accessible synthetic methods and evaluated for their anti-HIV activities in MT-4 cells. Preliminary biological evaluation indicated that most of the compounds exhibited marked inhibitory activity against the wild-type HIV-1 IIIB. Particularly, compound 7n was the most potent inhibitor against wild-type and K103N/Y181C double resistant mutant strain of HIV-1, possessing EC50 values of 0.02 μM and 7.6 μM, respectively, which were much better than or similar to nevirapine (NVP, EC50 = 0.15 μM, 2.9 μM) and delavirdine (DLV, EC50 = 0.07 μM, >36 μM). Besides, some other compounds, 5b, 7c, 7e, 7f, and 7m, were also endowed with favorable anti-HIV-1 potency (EC50 = 0.07, 0.05, 0.05, 0.07, and 0.05 μM, respectively), which were better than or similar to those of NVP and DLV, suggesting a high potential to further develop this type of bridgehead nitrogen heterocycle as a novel class of NNRTIs with improved antiviral efficacy and resistance profile. The selected compound, 7i, was found moderately inhibitory towards RT (IC50 = 0.39 μM), which was higher than for ETV (IC50 = 0.56 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were detailed in this manuscript.

Keywords: Bridgehead nitrogen heterocycle; DAPY; Molecular modeling; Structure–activity relationships; [1,2,4]Triazolo[1,5-a]pyrimidine; anti-HIV activities.

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 / genetics
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Models, Molecular
  • Mutation
  • Nitrogen / chemistry*
  • Protein Conformation
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship

Substances

  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • Nitrogen