A prodrug approach toward the development of water soluble fluoroquinolones and structure--activity relationships of quinoline-3-carboxylic acids

Journal of Medicinal Chemistry
William R BakerJoseph H Therrien

Abstract

A fluoroquinolone prodrug, PA2808, was prepared and shown to convert to the highly active parent drug PA2789. In vitro and in vivo activation of PA2808 by alkaline phosphatase was demonstrated using disk diffusion and rat lung infection models. The water solubility of PA2808 showed a marked increase compared to PA2789 over a pH range suitable for aerosol drug delivery. A total of 48 analogues based on PA2789 were prepared and screened against a panel of Gram-positive and Gram-negative pathogens. Incorporating a cyclopropane-fused pyrrolidine (amine) at C-7 resulted in some of the most active analogues.

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Citations

Oct 11, 2013·Acta Crystallographica. Section E, Structure Reports Online·Kamal SweidanAhmed Al-Sheikhb
Jul 14, 2007·Advanced Drug Delivery Reviews·Valentino J Stella, Kwame W Nti-Addae
Mar 6, 2007·European Journal of Medicinal Chemistry·Yiyun ChengTongwen Xu
Feb 9, 2007·Organic Letters·Ryan A Altman, Stephen L Buchwald

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