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

作者：Angehrn Peter; Goetschi Erwin^*; Gmuender Hans; Hebeisen Paul; Hennig Michael; Kuhn Bernd; Luebbers Thomas; Reindl Peter; Ricklin Fabienne; Schmitt Hoffmann Anne

来源：Journal of Medicinal Chemistry, 2011, 54(7): 2207-2224.

DOI：10.1021/jm1014023

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 12-14-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 "dilactam" subclass of DNA gyrase inhibitors of inherently higher polarity. After adjusting their lipophilicity by methyl halogen 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.

• 出版日期2011-4-14