A New DNA Gyrase Inhibitor Subclass of the Cyclothialidine Family Based on a Bicyclic Dilactam鈭扡actone Scaffold. Synthesis and Antibacterial Properties

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• 作者：Peter Angehrn ; Erwin Goetschi ; Hans Gmuender ; Paul Hebeisen ; Michael Hennig ; Bernd Kuhn ; Thomas Luebbers ; Peter Reindl ; Fabienne Ricklin ; Anne Schmitt-Hoffmann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2207-2224
• 全文大小：1286K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

The DNA gyrase inhibitor cyclothialidine had been shown to be a valuable lead structure for the discovery of new antibacterial classes able to overcome bacterial resistance to clinically used drugs. Bicyclic lactone derivatives containing in their 12鈭?4-membered ring a thioamide functionality were reported previously to exhibit potent antibacterial activity against Gram-positive bacteria. Moderate in vivo efficacy, however, was demonstrated only for derivatives bearing hydrophilic substituents, which were found to have a favorable impact on pharmcokinetics, and to reduce metabolic degradation, in particular glucuronidation. The incorporation of an additional amide unit into the 14-membered monolactam-lactone scaffold of cyclothialidine analogues provided a new 鈥渄ilactam鈥?subclass of DNA gyrase inhibitors of inherently higher polarity. After adjusting their lipophilicity by methyl鈭抙alogen exchange at the benzene ring, compounds of this series did not require the thioamide functionality to exert a decent antibacterial potency and consequently exhibited improved pharmacokinetic properties resulting in a pronounced in vivo efficacy in a mouse septicaemia infection model.