Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis

Tuberculosis
(TB) remains a serious public health challenge, and
the research and development of new anti-TB drugs is an essential
component of the global strategy to eradicate TB. In this work, we
discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused
lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared
to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability,
cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics
in animals. Compound 19c demonstrated an excellent safety
profile in a battery of safety assays, including mitochondrial protein
synthesis, hERG K+, hCav1.2, and Nav1.5 channels, monoamine
oxidase, and genotoxicity. In a 4 week repeated dose toxicology study
in rats, 19c appeared to have less bone marrow suppression
than linezolid, which has been a major liability of the oxazolidinone
class.