Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation

Bioorg Med Chem. 2015 Nov 1;23(21):7053-60. doi: 10.1016/j.bmc.2015.09.029. Epub 2015 Sep 21.

Abstract

Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess K(i) values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.

Keywords: 3-Bromo isoxazoline; Dipeptide-like; Inhibitor; Molecular modeling; Rhodesain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacology
  • Binding Sites
  • Cell Line
  • Cell Survival / drug effects
  • Cysteine Endopeptidases / chemistry*
  • Cysteine Endopeptidases / metabolism
  • Cysteine Endopeptidases / pharmacology
  • Cysteine Proteases / chemistry
  • Cysteine Proteases / metabolism
  • Cysteine Proteinase Inhibitors / chemistry
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Dipeptides / chemistry
  • Drug Design
  • Isoxazoles / chemistry*
  • Mice
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Trypanosoma brucei brucei / drug effects

Substances

  • Antiprotozoal Agents
  • Cysteine Proteinase Inhibitors
  • Dipeptides
  • Isoxazoles
  • Cysteine Proteases
  • Cysteine Endopeptidases
  • rhodesain