Improvement of both plasmepsin inhibitory activity and antimalarial activity by 2-aminoethylamino substitution

Bioorg Med Chem Lett. 2010 Aug 15;20(16):4836-9. doi: 10.1016/j.bmcl.2010.06.099. Epub 2010 Jun 25.

Abstract

We attached 2-aminoethylamino groups to allophenylnorstatine-containing plasmepsin (Plm) inhibitors and investigated SAR of the methyl or ethyl substitutions on the amino groups. Unexpectedly, compounds 22 (KNI-10743) and 25 (KNI-10742) exhibited extremely potent Plm II inhibitory activities (K(i)<0.1 nM). Moreover, among our peptidomimetic Plm inhibitors, we identified the compounds with the highest antimalarial activity using a SYBR Green I-based fluorescence assay.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / pharmacology
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Binding Sites
  • Computer Simulation
  • Ethylenediamines / chemical synthesis
  • Ethylenediamines / chemistry*
  • Ethylenediamines / pharmacology
  • Phenylbutyrates / chemistry
  • Protease Inhibitors / chemistry*
  • Protease Inhibitors / pharmacology
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology

Substances

  • Antimalarials
  • Ethylenediamines
  • KNI 10742
  • KNI 10743
  • Phenylbutyrates
  • Protease Inhibitors
  • Protozoan Proteins
  • Thiazoles
  • 3-amino-2-hydroxy-4-phenylbutanoic acid
  • Aspartic Acid Endopeptidases
  • plasmepsin II