Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids.
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.
Breuning
Alexander
A
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, Germany.
Degel
Björn
B
Schulz
Franziska
F
Büchold
Christian
C
Stempka
Martin
M
Machon
Uwe
U
Heppner
Saskia
S
Gelhaus
Christoph
C
Leippe
Matthias
M
Leyh
Matthias
M
Kisker
Caroline
C
Rath
Jennifer
J
Stich
August
A
Gut
Jiri
J
Rosenthal
Philip J
PJ
Schmuck
Carsten
C
Schirmeister
Tanja
T
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
D000962:Antimalarials; D015853:Cysteine Proteinase Inhibitors; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C416224:falcipain 2; C443101:falcipain 3; C446033:rhodesain