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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 5; pp. 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: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2013; Elsevier
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial topoisomerases; Chemistry; Chemistry, Medicinal; Chemistry, Organic; 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; Life Sciences & Biomedicine; Models, Molecular; ParE; Pharmacology & Pharmacy; Physical Sciences; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolopyrimidine; Science & Technology; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; topology; GyrB; Bacterial topoisomerases; ParE; Pyrrolopyrimidine; Inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.032

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.