Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach

Bioorg Med Chem. 2016 Sep 15;24(18):4424-4433. doi: 10.1016/j.bmc.2016.07.041. Epub 2016 Jul 21.

Abstract

By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50 in the range of 0.78-4.46μM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50=0.78μM, SI=24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50=5.64μM) and double mutant strain RES056 (EC50=22.24μM). Preliminary structure-activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization.

Keywords: AIDS; Anti-HIV activity; Bioisosterism; Drug design; HIV-1; NNRTIs; Purinylthioacetanilide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemistry
  • Acetanilides / pharmacology*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Carbon-13 Magnetic Resonance Spectroscopy
  • HIV-1 / drug effects*
  • Models, Molecular
  • Proton Magnetic Resonance Spectroscopy
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship

Substances

  • Acetanilides
  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • thioacetanilide