Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: Optimization of isothiazoloquinolones (ITQs) for potency against multi-drug resistant S. aureus has previously defined the optimal tricyclic core construct and its substituents. The 7-position was further optimized for anti-MRSA activity, specifically altering substitution patterns and stereochemistry of a 3-aminomethylpyrrolidine group. Methods: Stereospecific synthesis of substituted 3-aminomethylpyrrolidines was used to create a series of related ITQ analogs. Antibacterial activities and general cytotoxicity were assessed along with target enzyme (gyrase and topoisomerase IV) activity of select compounds using standard methodologies. Results: Most analogs were highly active against S. aureus and E. coli. Potency was generally diminished by N-substitution on nitrogen and improved with substitutions alpha to the terminal nitrogen. The R-configuration of the 3-position of the pyrrolidine was optimal for MRSA potency. Many of these analogs had MICs below 1 ug/mL against quinolone-resistant MRSA. This could be attributed to the increased effectiveness against wild-type and mutant S. aureus gyrase relative to quinolones. Conclusions: Optimization of substitution patterns of 7-(3-aminomethylpyrrolidine)-ITQs lead to exceptionally potent compounds against MRSA.