Novel bacterial topoisomerase inhibitors
(NBTIs) are among the
most promising new antibiotics in preclinical/clinical development.
We previously reported dioxane-linked NBTIs with potent antistaphylococcal
activity and reduced hERG inhibition, a key safety liability. Herein,
polarity-focused optimization enabled the delineation of clear structure–property
relationships for both microsomal metabolic stability and hERG inhibition,
resulting in the identification of lead compound 79.
This molecule demonstrates potent antibacterial activity against diverse
Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase
IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy
in a murine model of methicillin-resistant Staphylococcus
aureus infection.
Antibacterial resistance continues its devastation of available therapies. Novel bacterial topoisomerase inhibitors (NBTIs) offer one solution to this critical issue. Two series of amine NBTIs bearing tricyclic DNA-binding moieties as well as amide NBTIs with a bicyclic DNA-binding moiety were synthesized and evaluated against methicillin-resistant Staphylococcus aureus (MRSA). Additionally, these compounds and a series of bicyclic amine analogues displayed high activity against susceptible and drug-resistant Neisseria gonorrhoeae, expanding the spectrum of these dioxane-linked NBTIs.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.