ge-2270-a and Sepsis

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Carboxylic Acids; Crystallography, X-Ray; Drug Resistance, Bacterial; Female; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Male; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Conformation; Mutation; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Sepsis; Solubility; Stereoisomerism; Structure-Activity Relationship; Thiazoles