Screening of Protease Inhibitors as Antiplasmodial Agents. Part I: Aziridines and Epoxides

• Published in: ChemMedChem 2007-08, Vol.2 (8), p.1214-1224
• Main Authors: Schulz, Franziska, Gelhaus, Christoph, Degel, Björn, Vicik, Radim, Heppner, Saskia, Breuning, Alexander, Leippe, Matthias, Gut, Jiri, Rosenthal, Philip J., Schirmeister, Tanja
• Format: Article
• Language: English
• Subjects: Animals; Antimalarials - chemistry; Antimalarials - pharmacology; aziridine; Aziridines - pharmacology; epoxide; Epoxy Compounds - pharmacology; falcipain; inhibitor; malaria; Plasmodium falciparum - drug effects; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Stereoisomerism
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200700070

A broad protease‐based and cell‐based screening of protease inhibitors yielded the aziridine‐2‐carboxylic acid derivative 2 a and the N‐acylated aziridine‐2,3‐dicarboxylic acid derivatives 32 a and 34 b as the most potent inhibitors of falcipain‐2 and falcipain‐3 (IC50 falcipain‐2: 0.079–5.4 μM, falcipain‐3: 0.25–39.8 μM). As the compounds also display in vitro activity against the P. falciparum parasite in the submicromolar and low micromolar range, these compound classes are leads for new antiplasmodial falcipain inhibitors. Proteases, in particular cysteine proteases, of malaria parasites play pivotal roles in the process of the disease. Therefore, the inhibition of cysteine proteases presents a promising strategy for combating the infection. A broad protease‐ and cell‐based screening of 88 protease inhibitors containing an epoxide or aziridine ring yielded highly potent falcipain‐2 and falcipain‐3 inhibitors with antiplasmodial activity in the submicromolar range.