A new DNA gyrase inhibitor subclass of the cyclothialidine family based on a bicyclic dilactam-lactone scaffold. Synthesis and antibacterial properties.

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.