2 H-1,2,3-Triazole-Based Dipeptidyl Nitriles: Potent, Selective, and Trypanocidal Rhodesain Inhibitors by Structure-Based Design
| Autor: | Marcel Kaiser, Wolfgang Haap, Sarah Saint-Auret, Franz Schuler, Tanja Schirmeister, Rainer E. Martin, François Diederich, Bernd Kuhn, Reto Brun, Maude Giroud, Christoph Kuratli |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Trypanosoma brucei rhodesiense Stereochemistry Swine Trypanosoma cruzi Plasmodium falciparum Triazole Protozoan Proteins Cysteine Proteinase Inhibitors Ligands 01 natural sciences Cell Line Cathepsin L 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Drug Discovery Nitriles Structure–activity relationship Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Trypanocidal agent Binding Sites biology Molecular Structure 010405 organic chemistry Chemistry Dipeptides Triazoles Cysteine protease Trypanocidal Agents 0104 chemical sciences Rats Cysteine Endopeptidases 030104 developmental biology Drug Design biology.protein Microsomes Liver Molecular Medicine Female Leishmania donovani |
| Zdroj: | Journal of medicinal chemistry. 61(8) |
| ISSN: | 1520-4804 |
| Popis: | 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 (Ki values) and in vitro cell-growth of Trypanosoma brucei rhodesiense (IC50 values) were measured in the nanomolar range. Triazole-based ligands, obtained by a safe, gram-scale flow production of ethyl 1H-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, para... |
| Databáze: | OpenAIRE |
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