Abstract
In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.
Keywords:
Michael acceptors; Trypanosoma brucei; cathepsin L; rhodesain; selectivity.
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology*
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Dose-Response Relationship, Drug
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Ketones / chemical synthesis
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Ketones / chemistry
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Ketones / pharmacology*
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Molecular Structure
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Parasitic Sensitivity Tests
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Peptides / chemical synthesis
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Peptides / chemistry
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Peptides / pharmacology*
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Structure-Activity Relationship
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacology*
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Trypanosoma brucei brucei / drug effects*
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Trypanosoma brucei brucei / metabolism
Substances
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Cysteine Proteinase Inhibitors
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Ketones
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Peptides
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Trypanocidal Agents
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Cysteine Endopeptidases
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rhodesain