Synthesis and anti-HIV activity of aryl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazones as potent non-nucleoside reverse transcriptase inhibitors

ChemMedChem. 2011 Dec 9;6(12):2225-32. doi: 10.1002/cmdc.201100334. Epub 2011 Sep 8.

Abstract

A series of novel diarylpyrimidines (DAPYs) with a ketone hydrazone substituent on the methylene linker between the pyrimidine nucleus and the aryl moiety at the C-4 position were synthesized, and their antiviral activity against human immunodeficiency virus (HIV)-1 in MT-4 cells was evaluated. Most compounds of this class exhibited excellent activity against wild-type HIV-1, with EC(50) values in the range of 1.7-13.2 nM. Of these compounds, 2-bromophenyl-2-[(4-cyanophenyl)amino]-4-pyrimidinone hydrazone (9k) displayed the most potent anti-HIV-1 activity (EC(50) =1.7±0.6 nM), with excellent selectivity for infected over uninfected cells (SI=5762). In addition, the 4-methyl phenyl analogue 9d (EC(50) =2.4±0.2 nM, SI=18461) showed broad spectrum HIV inhibitory activity, with EC(50) values of 2.4±0.2 nM against wild-type HIV-1, 5.3±0.4 μM against HIV-1 double-mutated strain RES056 (K103N+Y181C), and 5.5 μM against HIV-2 ROD strain. Furthermore, structure-activity relationship (SAR) data and molecular modeling results for these compounds are also discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Binding Sites
  • Cell Line
  • Computer Simulation
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Hydrazines / chemistry*
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Hydrazines
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • hydrazine
  • HIV Reverse Transcriptase