J Med Chem. 2021 Mar 11. doi: 10.1021/acs.jmedchem.0c02153. Online ahead of print.
A series of conformationally constrained novel benzo[1,3]oxazinyloxazolidinones were designed, synthesized, and evaluated on their activities against Mycobacterium tuberculosis, Gram-positive bacteria, and Gram-negative bacteria. The studies identified a new compound 20aa that displayed good to excellent antibacterial and antitubercular profiles against drug-resistant TB strains (MIC = 0.48-0.82 μg/mL), MRSA (MIC = 0.25-0.5 μg/mL), MRSE (MIC = 1 μg/mL), VISA (MIC = 0.25 μg/mL), and VRE (MIC = 0.25 μg/mL) and some linezolid-resistant strains (MIC 1-2 μg/mL). Compound 20aa was demonstrated as a promising candidate through ADME/T evaluation including microsomal stability, cytotoxicity, and inhibition of hERG and monoamine oxidase. Notably, 20aa showed excellent mouse PK profile with high plasma exposure (AUC0-∞ = 78 669 h·ng/mL), high peak plasma concentration (Cmax = 10 253 ng/mL), appropriate half-life of 3.76 h, and superior oral bioavailability (128%). The present study not only successfully provides a novel benzo[1,3]oxazinyloxazolidinone scaffold with superior druggability but also lays a good foundation for new antibacterial drug development.