F1-2026. Novel DNA Gyrase Inhibitiors: The Effect of Pyrrolamide Linker Variations Upon Potency
Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: The pyrrolamides are a new class of antibacterials that inhibit DNA gyrase by competing with ATP binding, resulting in inhibition of DNA synthesis and bacterial cell death. Presented herein are new analogs in the pyrrolamide series with varying linker moieties and the impact of these modifications on their biochemical and antibacterial activity. Methods: Compounds were synthesized by either amine displacement or Suzuki Coupling of phenylboronic acids with halogen substituted aromatic esters. Inhibition of DNA gyrase and antibacterial activity were evaluated in vitro. X-ray crystallography and computational docking were used to rationalize the SAR. Results: Biochemical and antibacterial potency for many analogs was excellent, with Staphylococcus aureus Gyrase IC50 values in the range of 10 to 700 nM and MIC values for Streptococcus pneumoniae in the range 0.13 to 32 ug/mL. Generally, analogs incorporating azepine linkers were found to be more potent than those with embedded pyrrolidines (e.g. S. aureus IC50 for 1 and 2 = 71 nM and 690 nM, respectively.) Conclusions: Variations to the linker of the pyrrolamide series such as 1 and 2 generated potent antibacterial agents. The most potent compounds from this chemical class had linkers that imparted a coplanar topology to the molecule and optimal interactions with the target’s binding pocket.
Ann Eakin, PhD1, Brian Sherer2, Gregory Basarab3, Kenneth Hull3, Shanta Bist3, Sheila Hauck3 and  B. Sherer, None., (1)Infection Discovery, Cancer and Infection Research Area, AstraZeneca R&D Boston, (2)AstraZeneca R&D Boston, Waltham, MA, (3)AstraZeneca R&D Boston

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