Abstract
A series of 6-hetaryloxy benzoxaborole compounds was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the changes in antimalarial activity which result from 6-aryloxy structural variation, substituent modification on the pyrazine ring, and optimization of the side chain ester group. This SAR study discovered highly potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 27-34) with IC50s = 0.2-22 nM against cultured Plasmodium falciparum W2 and 3D7 strains. Compound 9 also demonstrated excellent in vivo efficacy against P. berghei in infected mice (ED90 = 7.0 mg/kg).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / chemistry*
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Antimalarials / pharmacology*
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Boron Compounds / chemistry*
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Boron Compounds / pharmacology*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry*
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Cell Survival / drug effects
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Female
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Humans
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Jurkat Cells
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Malaria, Falciparum / drug therapy*
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Malaria, Falciparum / parasitology
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Mice
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Microsomes, Liver / drug effects*
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Plasmodium falciparum / drug effects*
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Pyrazines / chemistry*
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Pyrazines / pharmacology*
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Structure-Activity Relationship
Substances
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Antimalarials
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Boron Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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Pyrazines