Design and evaluation of Trypanosoma brucei metacaspase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 6; pp. 2001 - 2006
• Main Authors: Berg, Maya, Veken, Pieter Van der, Joossens, Jurgen, Muthusamy, Venkatraj, Breugelmans, Matthias, Moss, Catherine X., Rudolf, Jana, Cos, Paul, Coombs, Graham H., Maes, Louis, Haemers, Achiel, Mottram, Jeremy C., Augustyns, Koen
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2010; Elsevier
• Subjects: African trypanosomiasis; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antibodies; Antiparasitic agents; Biological and medical sciences; Caspase Inhibitors; Caspases - metabolism; Catalysis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Drug Design; Inhibitor; Medical sciences; Metacaspase; Pharmacology. Drug treatments; Protease inhibitor; Sleeping sickness; Substrate Specificity; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - enzymology; Inhibitor; Sleeping sickness; Trypanosoma brucei; Metacaspase; African trypanosomiasis; Protease inhibitor; Protozoal disease; Cysteine endopeptidases; Selectivity; Chemical synthesis; Valine derivatives; Trypanosomiasis; Kinetoplastida; Protozoa; Enzyme; Peptidomimetic compound; Enzyme inhibitor; Guanidines; Parasitosis; African sickness; Benzothiazole derivatives; In vitro; Biological activity; Infection; Peptidases; Hydrolases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.099

We present the first inhibitors of metacaspase 2 of Trypanosoma brucei with low micromolar enzymatic activity. These compounds possess modest antiparasitic activity and have excellent selectivity when compared to mammalian caspases. Metacaspase (MCA) is an important enzyme in Trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. Therefore MCA constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. A first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. In this Letter we present the first inhibitors of TbMCA2 with low micromolar enzymatic and antiparasitic activity in vitro combined with low cytotoxicity.