Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity

The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor developm...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (5), p.1529-1536
Main Authors: Tari, Leslie W., Trzoss, Michael, Bensen, Daniel C., Li, Xiaoming, Chen, Zhiyong, Lam, Thanh, Zhang, Junhu, Creighton, Christopher J., Cunningham, Mark L., Kwan, Bryan, Stidham, Mark, Shaw, Karen J., Lightstone, Felice C., Wong, Sergio E., Nguyen, Toan B., Nix, Jay, Finn, John
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Bacterial topoisomerases
chemistry
DNA
DNA Gyrase - metabolism
DNA topoisomerase
DNA topoisomerase (ATP-hydrolysing)
DNA Topoisomerase IV - antagonists & inhibitors
DNA Topoisomerase IV - chemistry
Drug Design
enzyme activity
GyrB
Inhibitor
Models, Molecular
ParE
Pyrimidines - chemistry
Pyrimidines - pharmacology
Pyrroles - chemistry
Pyrroles - pharmacology
Pyrrolopyrimidine
Structure-Activity Relationship
Topoisomerase II Inhibitors - chemistry
Topoisomerase II Inhibitors - pharmacology
topology
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Summary:The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.11.032