Pyridone-conjugated monobactam antibiotics with Gram-negative activity

…, MJ Mitton-Fry, JT Arcari, R Barham…

Index: Brown, Matthew F.; Mitton-Fry, Mark J.; Arcari, Joel T.; Barham, Rose; Casavant, Jeffrey; Gerstenberger, Brian S.; Han, Seungil; Hardink, Joel R.; Harris, Thomas M.; Hoang, Thuy; Huband, Michael D.; Lall, Manjinder S.; Lemmon, M. Megan; Li, Chao; Lin, Jian; McCurdy, Sandra P.; McElroy, Eric; McPherson, Craig; Marr, Eric S.; Mueller, John P.; Mullins, Lisa; Nikitenko, Antonia A.; Noe, Mark C.; Penzien, Joseph; Plummer, Mark S.; Schuff, Brandon P.; Shanmugasundaram, Veerabahu; Starr, Jeremy T.; Sun, Jianmin; Tomaras, Andrew; Young, Jennifer A.; Zaniewski, Richard P. Journal of Medicinal Chemistry, 2013 , vol. 56, # 13 p. 5541 - 5552

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Citation Number: 17

Abstract

Herein we describe the structure-aided design and synthesis of a series of pyridone- conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is ...