Design, Synthesis, and Biological Evaluation of Novel Benzoyl Diarylamine/ether Derivatives as Potential Anti-HIV-1 Agents

Chem Biol Drug Des. 2015 Sep;86(3):333-43. doi: 10.1111/cbdd.12497. Epub 2015 Jan 12.

Abstract

A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for their activity against human immunodeficiency virus (HIV) in MT-4 cells. Three compounds (3b, 5a, and 6a1) exhibited moderate activities against wild-type (wt) HIV-1 with EC50 values ranging from 11 to 56 μm. Among them, compound 5a was the most potent inhibitor with a novel chemical skeleton, affording a new lead compound for further molecular optimization. An enzyme assay was also implemented to confirm the binding target of the active compounds represented by 6a1. Molecular simulation studies on compound 5a, 6a1, and 7a4 were carried out to understand their binding mode with wt HIV-1 reverse transcriptase (RT) and provided useful information for further rational design of NNRTIs.

Keywords: HIV-1; NNRTIs; anti-HIV-1 activity; molecular modeling; synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry*
  • Aniline Compounds / pharmacology*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Drug Design
  • Ether / analogs & derivatives*
  • Ether / chemical synthesis
  • Ether / chemistry
  • Ether / pharmacology
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Models, Molecular
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology*

Substances

  • Aniline Compounds
  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • Ether