Abstract
Pyrrolidinyl- and thiazolidinyl- dipeptide derivatives, featuring either a vinyl sulfone-, a 2-ketobenzothiazole-, a nitrile-, or a benzimidazole group at the C-terminus, were designed and synthesized as potential inhibitors of the prolyl-specific Tc80 proteinase from Trypanosoma cruzi, the agent of Chagas' disease. These compounds were evaluated in vitro towards the target enzyme which was classified as a serine protease belonging to the prolyl oligopeptidase family (EC 3.4.21.26). A peptidyl nitrile and two peptidyl alpha-ketobenzothiazoles were shown to be potent reversible and competitive inhibitors of Tc 80 proteinase, with K(i) values in the range 38-219 nM, and compared advantageously with some known mammalian prolyl oligopeptidase inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chromatography, Gel
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Dipeptides / chemical synthesis*
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Dipeptides / pharmacology
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Kinetics
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Prolyl Oligopeptidases
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Protozoan Proteins
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacology
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Serine Endopeptidases / metabolism*
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology
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Spectrometry, Fluorescence
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Substrate Specificity
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacology
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / pharmacology
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Trypanosoma cruzi / drug effects*
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Trypanosoma cruzi / enzymology*
Substances
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Dipeptides
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Protozoan Proteins
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Pyrrolidines
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Serine Proteinase Inhibitors
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Thiazoles
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Trypanocidal Agents
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Serine Endopeptidases
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Prolyl Oligopeptidases
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Tc80 prolyl oligopeptidase, Trypanosoma cruzi