Indolylarylsulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: new cyclic substituents at indole-2-carboxamide

J Med Chem. 2011 Mar 24;54(6):1587-98. doi: 10.1021/jm101614j. Epub 2011 Mar 2.

Abstract

New indolylarylsulfone derivatives bearing cyclic substituents at indole-2-carboxamide linked through a methylene/ethylene spacer were potent inhibitors of the WT HIV-1 replication in CEM and PBMC cells with inhibitory concentrations in the low nanomolar range. Against the mutant L100I and K103N RT HIV-1 strains in MT-4 cells, compounds 20, 24-26, 36, and 40 showed antiviral potency superior to that of NVP and EFV. Against these mutant strains, derivatives 20, 24-26, and 40 were equipotent to ETV. Molecular docking experiments on this novel series of IAS analogues have also suggested that the H-bond interaction between the nitrogen atom in the carboxamide chain of IAS and Glu138:B is important in the binding of these compounds. These results are in accordance with the experimental data obtained on the WT and on the mutant HIV-1 strains tested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Benzoxazines / pharmacology
  • Cells, Cultured
  • Cyclopropanes
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Models, Molecular
  • Molecular Conformation
  • Mutation
  • Nevirapine / pharmacology
  • Nitriles
  • Protein Binding
  • Pyridazines / pharmacology
  • Pyrimidines
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Indoles
  • Nitriles
  • Pyridazines
  • Pyrimidines
  • Reverse Transcriptase Inhibitors
  • Sulfones
  • etravirine
  • Nevirapine
  • HIV Reverse Transcriptase
  • efavirenz