부산대학교 도서관

Novel non-fluoroquinolone inhibitors of bacterial typeII topoisomerases (DNA gyrase and topoisomerase IV) are of interestfor the development of new antibacterial agents that are not impactedby target-mediated cross-resistance with fluoroquinolones. N-Linkedamino piperidines, such as 7a, generally show potentantibacterial activity, including against quinolone-resistant isolates,but suffer from hERG inhibition (IC50= 44 μM for 7a) and QT prolongation in vivo. We now disclose the findingthat new analogues of 7awith reduced pKadue to substitution with an electron-withdrawing substituentin the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7abut showed significantly less hERG inhibition (IC50=233 μM for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacyagainst a MRSA strain in a mouse infection model, and an improvedin vivo QT profile as measured in a guinea pig in vivo model. As aresult of its promising activity, R,S-7cwas advanced into phase I clinical studies. [ABSTRACT FROM AUTHOR]