Michael Acceptor Based Antiplasmodial and Antitrypanosomal Cysteine Protease Inhibitors with Unusual Amino Acids

• Published in: Journal of medicinal chemistry 2010-03, Vol.53 (5), p.1951-1963
• Main Authors: Breuning, Alexander, Degel, Björn, Schulz, Franziska, Büchold, Christian, Stempka, Martin, Machon, Uwe, Heppner, Saskia, Gelhaus, Christoph, Leippe, Matthias, Leyh, Matthias, Kisker, Caroline, Rath, Jennifer, Stich, August, Gut, Jiri, Rosenthal, Philip J, Schmuck, Carsten, Schirmeister, Tanja
• Format: Article
• Language: English
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei brucei - enzymology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm900946n

New peptidic Michael acceptor based cysteine protease inhibitors displaying antiparasitic activity were identified by testing a broad series of 45 compounds in total, containing Asn, Gln, or Phe. As target enzymes, falcipain-2 and -3 from P. falciparum and rhodesain from T. b. rhodesiense were used. In the case of the Asn/Gln containing compounds, the trityl-protected, diastereomeric E-configured vinylogous dipeptide esters 16 (Boc-(S)-Phg-(R/S)-vGln(Trt)-OEt) were discovered as most active inhibitors concerning both protease inhibition and antiparasitic acitivity, with inhibition constants in the submicromolar range. The compounds were shown to display time-dependent and competitive inhibition. In the case of the Phe containing compounds, the maleic acid derivatives 42 and 43 (BnO-Phe←Mal-Phe-OBn, BnO-Phe←Mal-Phe-Ala-OBn, Mal = maleic acid) displayed good inhibition of rhodesain as well as good antitrypanosomal activity, while the fumaric acid derived E-analogue 14 (BnO-Phe←Fum-Phe-OBn) only displayed inhibition of the target enzymes but no antiparasitic activity. Inhibition by these Phe derivatives was shown to be time-independent and competitive.