Chiral Indolylarylsulfone Non-Nucleoside Reverse Transcriptase Inhibitors as New Potent and Broad Spectrum Anti-HIV-1 Agents

J Med Chem. 2017 Aug 10;60(15):6528-6547. doi: 10.1021/acs.jmedchem.6b01906. Epub 2017 Jul 5.

Abstract

We designed and synthesized a series of chiral indolyarylsulfones (IASs) as new HIV-1 NNRTIs. The new IASs 8-37 showed potent inhibition of the HIV-1 WT NL4-3 strain and of the mutant K103N, Y181C, Y188L, and K103N-Y181C HIV-1 strains. Six racemic mixtures, 8, 23-25, 31, and 33, were separated at semipreparative level into their pure enantiomers. The (R)-8 enantiomer bearing the chiral (α-methylbenzyl) was superior to the (S)-counterpart. IAS derivatives bearing the (S) alanine unit, (S)-23, (S,R)-25, (S)-31, and (S)-33, were remarkably more potent than the corresponding (R)-enantiomers. Compound 23 protected hippocampal neuronal cells from the excitotoxic insult, while efavirenz (EFV) did not contrast the neurotoxic effect of glutamate. The present results highlight the chiral IASs as new NNRTIs with improved resistance profile against the mutant HIV-1 strains and reduced neurotoxic effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Cells, Cultured
  • Glutamic Acid / toxicity
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Indoles / toxicity
  • Lipopolysaccharides / pharmacology
  • Mice, Inbred C57BL
  • Microglia / cytology
  • Microglia / drug effects
  • Molecular Docking Simulation
  • Mutation
  • Neurons / cytology
  • Neurons / drug effects
  • Neuroprotective Agents / chemical synthesis
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / toxicity
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Reverse Transcriptase Inhibitors / toxicity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / pharmacology*
  • Sulfones / toxicity

Substances

  • 5-chloro-3-((3,5-dimethylphenyl)sulfonyl)-N-(1-oxo-1-((pyridin-4-ylmethyl)amino)propan-2-yl)-1H-indole-2-carboxamide
  • Anti-HIV Agents
  • Indoles
  • Lipopolysaccharides
  • Neuroprotective Agents
  • Reverse Transcriptase Inhibitors
  • Sulfones
  • Glutamic Acid