Abstract
Fluorination is a well-known strategy for improving the bioavailability of drug molecules. However, its impact on efficacy is not easily predicted. On the basis of inhibitor-bound protein crystal structures, we found a beneficial fluorination spot for inhibitors targeting methionyl-tRNA synthetase of Trypanosoma brucei. In particular, incorporating 5-fluoroimidazo[4,5-b]pyridine into inhibitors leads to central nervous system bioavailability and maintained or even improved efficacy.
Keywords:
bioavailability; brain penetration; fluorination; human African trypanosomiasis; methionyl-tRNA synthetase.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Methionine-tRNA Ligase / antagonists & inhibitors*
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Methionine-tRNA Ligase / genetics
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Methionine-tRNA Ligase / metabolism
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Mice
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Molecular Structure
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / genetics
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Protozoan Proteins / metabolism
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Pyridines / chemistry
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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 / enzymology
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Trypanosoma brucei brucei / genetics
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Trypanosomiasis, African / parasitology*
Substances
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Enzyme Inhibitors
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Protozoan Proteins
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Pyridines
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Trypanocidal Agents
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Methionine-tRNA Ligase
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pyridine