Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127439. doi: 10.1016/j.bmcl.2020.127439. Epub 2020 Jul 25.

Abstract

Cysteine protease B (CPB) can be targeted by reversible covalent inhibitors that could serve as antileishmanial compounds. Here, sixteen dipeptidyl nitrile derivatives were synthesized, tested against CPB, and analyzed using matched molecular pairs to determine the effects of stereochemistry and p-phenyl substitution on enzyme inhibition. The compound (S)-2-(((S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)amino)-N-(1-cyanocyclopropyl)-3-phenylpropanamide (5) was the most potent CPB inhibitor (pKi = 6.82), which was also selective for human cathepsin B (pKi < 5). The inversion of the stereochemistry from S to R was more detrimental to potency when placed at the P2 position than at P3. The p-Br derivatives were more potent than the p-CH3 and p-OCH3 derivatives, probably due to intermolecular interactions with the S3 subsite.

Keywords: Additive effect; Crystallographic structure; Dipeptidyl nitrile derivatives; Enzymatic inhibitors; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cathepsin B / metabolism
  • Cysteine / chemistry*
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / metabolism*
  • Drug Evaluation, Preclinical
  • Humans
  • Models, Molecular
  • Nitriles / chemical synthesis*
  • Protein Binding
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Cysteine Proteinase Inhibitors
  • Nitriles
  • Cysteine Endopeptidases
  • endopeptidase B
  • Cathepsin B
  • Cysteine