F1-2027. Novel DNA Gyrase Inhibitors: The Effect of Pyrrolamide Variations at Site 1 and Site 2 Upon Potency
Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: The pyrrolamides are a novel class of antibacterial agents that inhibit DNA gyrase resulting in inhibition of DNA synthesis and bacterial cell death. Presented herein are variation of site 2 moieties and the substituents on the site 1 pyrrole. The impact of these modifications on each analog’s biochemical and antibacterial activity is also presented. Methods: Compounds were synthesized by amine displacement of halogen substituted heterocycles and amide bond formation using coupling methods. Inhibition of DNA gyrase and antimicrobial activity were evaluated in vitro. X-ray crystallography and computational docking were used to design new analogs and rationalize SAR. Results: Biochemical and antibacterial activity for most analogs was excellent, with IC50 values against Staphylococcus aureus GyrB ATPase in the range of 10 to 600 nM and MIC values for Streptococcus pneumoniae in the range 0.08 to 32 ug/ml (CLSI methodology). Structure-activity studies at site 1 identified the 3,4-dichloropyrrole as one of the optimal site 1 groups and bicyclic heterocycles were the most potent site 2 moieties (e.g. Staphylococcus aureus GyrB ATPase Ki’s for 1 and 2 = 1 and 17 nM, respectively). Conclusions: Variations at site 1 and 2 of the pyrrolamide series, such as 1 and 2, led to the identification of potent antibacterial agents.
Alok Singh1, Ann Eakin, PhD2, Brian Sherer3, George Mullen1, Haihong Ni4, Jim Loch1, Kenneth Hull4, Oluyinka Green3, Shanta Bist4, Sheila Hauck4, Julie Demeritt1 and  K. Hull, None., (1)Astrazeneca, (2)Infection Discovery, Cancer and Infection Research Area, AstraZeneca R&D Boston, (3)AstraZeneca R&D Boston, Waltham, MA, (4)AstraZeneca R&D Boston


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