Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: Development of inhibitors with broad spectrum, Gram-negative antibacterial activity

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 5; pp. 1537 - 1543
• Main Authors: Trzoss, Micheal, Bensen, Daniel C., Li, Xiaoming, Chen, Zhiyong, Lam, Thanh, Zhang, Junhu, Creighton, Christopher J., Cunningham, Mark L., Kwan, Bryan, Stidham, Mark, Nelson, Kirk, Brown-Driver, Vickie, Castellano, Amanda, Shaw, Karen J., Lightstone, Felice C., Wong, Sergio E., Nguyen, Toan B., Finn, John, Tari, Leslie W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2013
• Subjects: Acinetobacter baumannii; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; antibacterial properties; antibiotics; Bacterial topoisomerases; chemistry; DNA Gyrase - chemistry; DNA Gyrase - metabolism; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerase IV - antagonists & inhibitors; DNA Topoisomerase IV - chemistry; Drug Design; Escherichia coli; Gram-negative antibacterial agents; GyrB; Humans; Inhibitor; ParE; pathogens; Pseudomonas aeruginosa; Pyrimidines - chemistry; Pyrimidines - pharmacology; Pyrroles - chemistry; Pyrroles - pharmacology; Pyrrolopyrimidine; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; GyrB; Bacterial topoisomerases; Pyrrolopyrimidine; ParE; Gram-negative antibacterial agents; Inhibitor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.11.073

The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity.