Abstract
We report on a target-based approach to identify possible Mycobacterium tuberculosis DXS inhibitors from the structure of a known transketolase inhibitor. A small focused library of analogs was assembled in order to begin elucidating some meaningful structure-activity relationships of 3-(4-chloro-phenyl)-5-benzyl-4H-pyrazolo[1,5-a]pyrimidin-7-one. Ultimately we found that 2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one, although still weak, was able to inhibit M. tuberculosis DXS with an IC(50) of 10.6 microM.
MeSH terms
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Antitubercular Agents / chemical synthesis*
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Antitubercular Agents / chemistry
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Antitubercular Agents / pharmacology*
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Combinatorial Chemistry Techniques
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Drug Design*
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Inhibitory Concentration 50
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Molecular Structure
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Mycobacterium tuberculosis / enzymology*
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Mycobacterium tuberculosis / genetics
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / 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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Transferases / antagonists & inhibitors
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Transferases / chemistry
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Transferases / genetics*
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Transferases / isolation & purification
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Transferases / metabolism*
Substances
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2-methyl-3-(4-fluorophenyl)-5-(4-methoxy-phenyl)-4H-pyrazolo(1,5-a)pyrimidin-7-one
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Antitubercular Agents
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Pyrazoles
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Pyrimidines
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Transferases
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deoxyxylulose-5-phosphate synthase