Abstract
Fatty acid biosynthesis is essential for bacterial survival. FabH, beta-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and -negative bacteria. Fifty-six 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 1-(5-(4-fluorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (12) and 1-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (13) were potent inhibitors of E. coli FabH.
Copyright 2010 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / antagonists & inhibitors*
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / metabolism
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Binding Sites
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Computer Simulation
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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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Escherichia coli Proteins / antagonists & inhibitors*
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Escherichia coli Proteins / metabolism
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Structure-Activity Relationship
Substances
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1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole
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Anti-Bacterial Agents
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Enzyme Inhibitors
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Escherichia coli Proteins
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Pyrazoles
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pyrazole
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3-ketoacyl-acyl carrier protein synthase III
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase