New potent C2-symmetric malaria plasmepsin I and II inhibitors

Bioorg Med Chem. 2003 Apr 3;11(7):1235-46. doi: 10.1016/s0968-0896(02)00643-0.

Abstract

A series of malaria plasmepsin (Plm) I and II inhibitors containing a C(2)-symmetric core structure have been synthesised and tested for protease inhibition activity. These compounds can be prepared using a straightforward synthesis involving a phenol nucleophilic ring opening of a diepoxide. Exemplar compounds synthesised exhibited remarkable inhibitory activity against both Plm I and II, notably 15c with K(i) values of 2.7nM and 0.25nM respectively, as well as showing >100-fold selectivity against Cathepsin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Animals
  • Antimalarials / chemical synthesis*
  • Antimalarials / pharmacology*
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Cathepsin D / chemistry
  • Humans
  • Hydrolysis
  • Indicators and Reagents
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology*
  • Protozoan Proteins
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antimalarials
  • Indicators and Reagents
  • Protease Inhibitors
  • Protozoan Proteins
  • Aspartic Acid Endopeptidases
  • plasmepsin
  • plasmepsin II
  • Cathepsin D