Preparation of novel anthranilic acids as antibacterial agents. Extensive evaluation of alternative amide bioisosteres connecting the A- and the B-rings

This paper describes the discovery of amide bioisosteres, an E-alkene and a trans cyclopropane, as potent antibacterial agents against Gram-positive organisms. In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently descri...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (10), p.2823-2827
Main Authors: Thorarensen, Atli, Wakefield, Brian D., Romero, Donna L., Marotti, Keith R., Sweeney, Michael T., Zurenko, Gary E., Rohrer, Douglas C., Han, Fusen, Bryant, Garold L.
Format: Article
Language:English
Subjects:
Amide
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Bioisoster
Biological and medical sciences
Cyclopropane
Drug Design
Drug Resistance, Bacterial
Medical sciences
Microbial Sensitivity Tests
Molecular Structure
ortho-Aminobenzoates - chemistry
ortho-Aminobenzoates - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:This paper describes the discovery of amide bioisosteres, an E-alkene and a trans cyclopropane, as potent antibacterial agents against Gram-positive organisms. In the past few years, a significant effort has been devoted by Pharmacia toward the discovery of novel antibiotics. We have recently described the identification of an anthranilic acid lead 1 and the optimization resulting in the advanced lead 2. In this report, we describe the preparation of several selected amide bioisosteres connecting the A- and the B-rings. The E-alkene provided a rigid analog with equal potency to the corresponding amide. This indicates that the amide is not a recognition element rather acts as an appropriate spatial linker of the two important aryl A and B rings. The work here clearly demonstrates that the amide linker can be replaced with several functionalities without significant deterioration in the MIC activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.02.055