3 research outputs found
Design, Synthesis, and Characterization of Novel Tetrahydropyran-Based Bacterial Topoisomerase Inhibitors with Potent Anti-Gram-Positive Activity
There is an urgent need for new antibacterial
drugs that are effective
against infections caused by multidrug-resistant pathogens. Novel
nonfluoroquinolone inhibitors of bacterial type II topoisomerases
(DNA gyrase and topoisomerase IV) have the potential to become such
drugs because they display potent antibacterial activity and exhibit
no target-mediated cross-resistance with fluoroquinolones. Bacterial
topoisomerase inhibitors that are built on a tetrahydropyran ring
linked to a bicyclic aromatic moiety through a <i>syn</i>-diol linker show potent anti-Gram-positive activity, covering isolates
with clinically relevant resistance phenotypes. For instance, analog <b>49c</b> was found to be a dual DNA gyrase–topoisomerase
IV inhibitor, with broad antibacterial activity and low propensity
for spontaneous resistance development, but suffered from high hERG
K<sup>+</sup> channel block. On the other hand, analog <b>49e</b> displayed lower hERG K<sup>+</sup> channel block while retaining
potent in vitro antibacterial activity and acceptable frequency for
resistance development. Furthermore, analog <b>49e</b> showed
moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model