2-(3,4-dihydro-4-oxothieno[2,3-d]pyrimidin-2-ylthio) acetamides as a new class of falcipain-2 inhibitors. 3. design, synthesis and biological evaluation

Molecules. 2009 Feb 16;14(2):785-97. doi: 10.3390/molecules14020785.


The cysteine protease falcipain-2 (FP-2) of Plasmodium falciparum is a principal cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites, making it become an attractive target enzyme for developing anti-malarial drugs. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on compound 1, which was identified by using structure-based virtual screening in conjunction with an enzyme inhibition assay. All compounds showed high inhibitory effect against FP-2 with IC(50)s of 1.46-11.38 microM, and the inhibitory activity of compound 2a was ~2 times greater than that of prototype compound 1. The preliminary SARs are summarized and should be helpful for future inhibitor design, and the novel scaffold presented here, with its potent inhibitory activity against FP-2, also has potential application in discovery of new anti-malarial drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides* / chemical synthesis
  • Acetamides* / chemistry
  • Acetamides* / metabolism
  • Animals
  • Antimalarials / chemical synthesis
  • Antimalarials / chemistry
  • Antimalarials / metabolism
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors* / chemical synthesis
  • Cysteine Proteinase Inhibitors* / chemistry
  • Cysteine Proteinase Inhibitors* / metabolism
  • Humans
  • Malaria, Falciparum / metabolism
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Plasmodium falciparum / enzymology
  • Structure-Activity Relationship


  • Acetamides
  • Antimalarials
  • Cysteine Proteinase Inhibitors
  • Cysteine Endopeptidases
  • falcipain 2