1207718-75-9Relevant academic research and scientific papers
Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids
Breuning, Alexander,Degel, Bj?rn,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
supporting information; experimental part, p. 1951 - 1963 (2010/08/03)
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 ?'-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 (BnOPhe←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.
