Abstract
Mycobacterium tuberculosis FabH, an essential enzyme in the mycolic acid biosynthetic pathway, is an attractive target for novel anti-tubercolosis agents. Structure-based design and synthesis of 1-(4-carboxybutyl)-4-(4-(substituted benzyloxy)phenyl)-1H-pyrrole-2-carboxylic acid derivatives 7a-h, a subset of eight potential FabH inhibitors, is described in this paper. The Vilsmeier-Haack reaction was employed as a key step. The structures of all the newly synthesized compounds were identified by IR, ¹H-NMR, ¹³C-NMR, ESI-MS and HRMS. The alamarBlue™ microassay was employed to evaluate the compounds 7a-h against Mycobacterium tuberculosis H₃₇Rv. The results demonstrate that the compound 7d possesses good in vitro antimycobacterial activity against Mycobacterium tuberculosis H₃₇Rv (Minimum Inhibitory Concentration value [MIC], 12.5 µg/mL).These compounds may prove useful in the discovery and development of new anti-tuberculosis drugs.
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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Antitubercular Agents / chemical synthesis*
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Antitubercular Agents / pharmacology
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Binding Sites
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Carboxylic Acids / chemical synthesis*
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Carboxylic Acids / pharmacology
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Drug Design
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Magnetic Resonance Spectroscopy
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Microbial Sensitivity Tests
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Microbial Viability / drug effects
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Models, Molecular
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / enzymology
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Mycobacterium tuberculosis / growth & development
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Mycolic Acids / metabolism
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Oxazines
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Protein Binding
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacology
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Spectrometry, Mass, Electrospray Ionization
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Spectrophotometry, Infrared
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Structure-Activity Relationship
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Xanthenes
Substances
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Antitubercular Agents
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Carboxylic Acids
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Enzyme Inhibitors
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Mycolic Acids
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Oxazines
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Pyrroles
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Xanthenes
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resazurin
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3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
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FabH protein, Mycobacterium tuberculosis