| Abstract
| - Cyclothialidine (1, Ro 09-1437) is a potent DNA gyrase inhibitor that was isolated fromStreptomyces filipinensis NR0484 and is a member of a new family of natural products. It actsby competitively inhibiting the ATPase activity exerted by the B subunit of DNA gyrase butbarely exhibits any growth inhibitory activity against intact bacterial cells, presumably due toinsufficient permeation of the cytoplasmic membrane. To explore the antibacterial potentialof 1, we developed a flexible synthetic route allowing for the systematic modification of itsstructure. From a first set of analogues, structure−activity relationships (SAR) were establishedfor different substitution patterns, and the 14-hydroxylated, bicyclic core (X) of 1 seemed to bethe structural prerequisite for DNA gyrase inhibitory activity. The variation of the lactonering size, however, revealed that activity can be found among 11- to 16-membered lactones,and even seco-analogues were shown to maintain some enzyme inhibitory properties, therebyreducing the minimal structural requirements to a rather simple, hydroxylated benzyl sulfide(XI). On the basis of these “minimal structures” a modification program afforded a number ofinhibitors that showed in vitro activity against Gram-positive bacteria. The best activities weredisplayed by 14-membered lactones, and representatives of this subclass exhibit excellent andbroad in vitro antibacterial activity against Gram-positive pathogens, including Staphylococcusaureus, Streptococcus pyogenes, and Enterococcus faecalis, and overcome resistance againstclinically used drugs. By improving the pharmacokinetic properties of the most activecompounds (94, 97), in particular by lowering their lipophilic properties, we were able to identifycongeners of cyclothialidine (1) that showed efficacy in vivo.
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