Discovery of piperidine-linked pyridine analogues as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

ChemMedChem. 2013 Jul;8(7):1117-26. doi: 10.1002/cmdc.201300130. Epub 2013 May 3.


In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Piperidines / chemistry*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Piperidines
  • Pyridines
  • Reverse Transcriptase Inhibitors
  • piperidine
  • HIV Reverse Transcriptase