Abstract
The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Drug Synergism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Folic Acid / chemistry
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Humans
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Hydrophobic and Hydrophilic Interactions
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Leishmania / drug effects
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Leishmania / enzymology*
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Leishmania major / drug effects
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Leishmania major / enzymology
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Leishmania mexicana / drug effects
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Leishmania mexicana / enzymology
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Molecular Docking Simulation
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Oxidative Stress / drug effects
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Oxidoreductases / antagonists & inhibitors*
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Protein Binding
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Pyrimethamine / 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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Trypanocidal Agents
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Folic Acid
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Oxidoreductases
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pteridine reductase
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Pyrimethamine