F1-2054. Optimization of the Anti-MRSA Activity of 3-Aminomethylpyrrolidine-Substituted Isothiazoloquinolones
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.
Akihiro Hashimoto, Ph D1, Barton Bradbury, PhD1, Christine Thoma1, David Nelson1, Edlaine Lucien1, Godwin Pais, Ph D1, Ha Kim, Ph D2, Jane Thanassi1, Jason Wiles, Ph D1, Jijun Cheng, PhD1, Michael Pucci, PhD3, Milind Deshpande, PhD1, Qiuping Wang, Ph D1, Steven Podos, PhD3 and  H. Y. Kim,
Achillion Pharmaceuticals Role(s): Employee, Received: Salary., (1)Achillion Pharmaceuticals, (2)Achillion Pharmaceuticals, New Haven, CT, CT, (3)Achillion Pharmaceuticals, New Haven, CT


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