Synthesis and Microbiological Evaluation of Novel Tetracyclic Fluoroquinolones

Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven‐membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbi...

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Bibliographic Details
Published in:ChemMedChem 2017-10, Vol.12 (20), p.1687-1692
Main Authors: Wagman, Allan S., Cirz, Ryan, McEnroe, Glenn, Aggen, James, Linsell, Martin S., Goldblum, Adam A., Lopez, Sara, Gomez, Marcela, Miller, George, Simons, Lloyd J., Belliotti, Thomas R., Harris, Christina R., Poel, Toni‐Jo, Melnick, Michael J., Gaston, Ricky D., Moser, Heinz E.
Format: Article
Language:English
Subjects:
Acinetobacter baumannii - drug effects
Antibiotics
antimicrobial spectrum
Bacteria
Fluoroquinolones
Fluoroquinolones - chemical synthesis
Fluoroquinolones - pharmacology
Gram-negative bacteria
gyrase
Lead compounds
Microbial Sensitivity Tests
Molecular Structure
Optimization
Pseudomonas aeruginosa - drug effects
Pyrrolidine
Stereochemistry
Structure-Activity Relationship
structure–activity relationships
Tetracyclines - chemical synthesis
Tetracyclines - pharmacology
topoisomerase
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Summary:Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven‐membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram‐positive and Gram‐negative bacteria. Focused optimization of seven‐membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression. Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. Installation of a seven‐membered ring between the pyrrolidine substituents and the C8 position on the FQ scaffold resulted in a remarkable enhancement in potency on both Gram‐positive and Gram‐negative bacteria. Focused optimization of seven‐membered ring composition, stereochemistry, and amine placement yielded the two lead compounds 36 and 40.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700426