Physicochemical property-driven optimization of diarylaniline compounds as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3719-23. doi: 10.1016/j.bmcl.2014.07.011. Epub 2014 Jul 11.

Abstract

Using physicochemical property-driven optimization, twelve new diarylaniline compounds (DAANs) (7a-h, 11a-b and 12a-b) were designed and synthesized. Among them, compounds 12a-b not only showed high potency (EC50 0.96-4.92 nM) against both wild-type and drug-resistant viral strains with the lowest fold change (FC 0.91 and 5.13), but also displayed acceptable drug-like properties based on aqueous solubility and lipophilicity (LE>0.3, LLE>5, LELP<10). The correlations between potency and physicochemical properties of these DAAN analogues are also described. Compounds 12a-b merit further development as potent clinical trial candidates against AIDS.

Keywords: Anti-HIV agents; Diarylaniline; NNRTIs; Physicochemical property.

Publication types

  • Research Support, N.I.H., Extramural
  • 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 / pharmacology*
  • Chemistry, Physical
  • Dose-Response Relationship, Drug
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

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