Giroud, Maude and Kuhn, Bernd and Saint-Auret, Sarah and Kuratli, Christoph and Martin, Rainer E. and Schuler, Franz and Diederich, François and Kaiser, Marcel and Brun, Reto and Schirmeister, Tanja and Haap, Wolfgang. (2018) 2 H-1,2,3-Triazole-based dipeptidyl nitriles : potent, selective, and Trypanocidal rhodesain inhibitors by structure-based design. Journal of medicinal chemistry, 61 (8). pp. 3370-3388.
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Official URL: https://edoc.unibas.ch/64806/
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Abstract
Macrocyclic inhibitors of rhodesain (RD), a parasitic cysteine protease and drug target for the treatment of human African trypanosomiasis, have shown low metabolic stability at the macrocyclic ether bridge. A series of acyclic dipeptidyl nitriles was developed using structure-based design (PDB ID: 6EX8 ). The selectivity against the closely related cysteine protease human cathepsin L (hCatL) was substantially improved, up to 507-fold. In the S2 pocket, 3,4-dichlorophenylalanine residues provided high trypanocidal activities. In the S3 pocket, aromatic residues provided enhanced selectivity against hCatL. RD inhibition ( K; i; values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC; 50; values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1 H-1,2,3-triazole-4-carboxylate, showed excellent metabolic stability in human liver microsomes and in vivo half-lives of up to 1.53 h in mice. When orally administered to infected mice, parasitaemia was reduced but without complete removal of the parasites.
Faculties and Departments: | 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser) |
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UniBasel Contributors: | Kaiser, Marcel and Brun, Reto |
Item Type: | Article, refereed |
Article Subtype: | Research Article |
Publisher: | American Chemical Society |
ISSN: | 0022-2623 |
Note: | Publication type according to Uni Basel Research Database: Journal article |
Identification Number: |
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Last Modified: | 03 Jul 2018 11:05 |
Deposited On: | 03 Jul 2018 11:05 |
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