ABSTRACT
The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacology , Protein Biosynthesis/drug effects , Staphylococcus aureus/drug effects , ortho-Aminobenzoates/chemistry , Anti-Bacterial Agents/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Indazoles/chemistry , Microbial Sensitivity Tests , Molecular Conformation , Molecular Structure , Structure-Activity RelationshipABSTRACT
The novel bacterial transcription/translation (TT) inhibitor 1 was identified through a combination of high throughput screening and exploratory medicinal chemistry. Initial optimization of the anthranilic acid moiety and sulfonamide amine diversity was accomplished via 1- and two-dimensional solution phase libraries, resulting in an improvement in the MIC of the lead from 64 to 8mug/mL (compound 4l). Subsequent modification of the central aromatic ring and further refinement of the sulfonamide amines required the development of a solid phase route on Wang resin. The resulting libraries generated a number of potent antibacterials with MICs of 1mug/mL (e.g., 10b, 12, and 13). During the course of this work, it became apparent that the antibacterial activity of the series is not fully correlated with TT inhibition, suggesting that at least one additional mechanism of action is operative.