Pyrrolidine Carboxamides as a Novel Class of Inhibitors of Enoyl Acyl Carrier Protein Reductase from Mycobacterium tuberculosis

In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2006-10, Vol.49 (21), p.6308-6323
Main Authors: He, Xin, Alian, Akram, Stroud, Robert, Ortiz de Montellano, Paul R
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antitubercular Agents - chemical synthesis
Antitubercular Agents - chemistry
Antitubercular Agents - pharmacology
Binding Sites
Biological and medical sciences
Crystallography, X-Ray
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors
Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - chemistry
Medical sciences
Microbial Sensitivity Tests
Models, Molecular
Molecular Structure
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - enzymology
Pharmacology. Drug treatments
Protein Binding
Pyrrolidines - chemical synthesis
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary:In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antituberculosis agent with novel structures. InhA, the enoyl acyl carrier protein reductase (ENR) from M. tuberculosis, is one of the key enzymes involved in the mycobacterial fatty acid elongation cycle and has been validated as an effective antimicrobial target. We report here the discovery, through high-throughput screening, of a series of pyrrolidine carboxamides as a novel class of potent InhA inhibitors. Crystal structures of InhA complexed with three inhibitors have been used to elucidate the inhibitor binding mode. The potency of the lead compound was improved over 160-fold by subsequent optimization through iterative microtiter library synthesis followed by in situ activity screening without purification. Resolution of racemic mixtures of several inhibitors indicate that only one enantiomer is active as an inhibitor of InhA.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060715y