Design, synthesis and preliminary SAR studies of novel N-arylmethyl substituted piperidine-linked aniline derivatives as potent HIV-1 NNRTIs

Bioorg Med Chem. 2014 Jan 1;22(1):633-42. doi: 10.1016/j.bmc.2013.10.033. Epub 2013 Nov 6.

Abstract

A series of novel N-arylmethyl substituted piperidine-linked aniline derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. All the new compounds showed moderate to potent activities against wild-type (wt) HIV-1 with an EC₅₀ range from 0.022 to 2.1 μM. Among them, compound 5a6 (EC₅₀=0.022 ± 0.0091 μM, SI >10,770) was confirmed to be the most potent and selective inhibitor, which proved more potent than DDI and DLV in a cell-based assay against wt HIV-1, and more efficient than NVP in an RT (reverse transcriptase) assay. Besides, it is worth noting that compound 7a1 retained moderate inhibitory activity (EC₅₀=4.8 ± 0.95 μM) against the HIV-1 double RT mutant strain (K103N/Y181C). The preliminary structure-activity relationship was discussed and rationalized by molecular simulation.

Keywords: AIDS; Anti-HIV-1 activity; HIV-1; NNRTIs; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / pharmacology
  • Drug Design
  • HIV-1 / genetics
  • HIV-1 / metabolism*
  • Humans
  • Models, Molecular
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Structure-Activity Relationship

Substances

  • Aniline Compounds
  • Anti-HIV Agents
  • Piperidines
  • piperidine
  • aniline