Abstract
To search for new cruzain inhibitors, the synthesis of a series of novel 2-(N'-benzylidenehydrazino)-4-trifluoromethyl-pyrimidines in a convergent manner is presented. The cruzain inhibitory activity of some of these compounds was evaluated and a binding model was proposed. All derivatives tested were active and the most significant inhibitory effect (80% at 100 microM) and IC(50) value (85 microM) were obtained from the 2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine. Although further structural optimization to improve solubility is necessary, the molecular docking studies suggest that these inhibitors occupy the S2 pocket without irreversible enzyme inactivation, through hydrophobic interactions, thus, indicating a desirable mode of interaction for the design of novel inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cysteine Endopeptidases / chemistry
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Cysteine Endopeptidases / pharmacology
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Hydrazines / chemical synthesis
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Hydrazines / chemistry
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Hydrazines / pharmacology*
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / chemistry
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Protozoan Proteins / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / 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
Substances
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2-(N'-4-chloro-benzylidenehydrazino)-4-trifluoromethyl-pyrimidine
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Enzyme Inhibitors
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Hydrazines
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Protozoan Proteins
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Pyrimidines
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Trypanocidal Agents
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Cysteine Endopeptidases
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cruzain, Trypanosoma cruzi