Identification of Novel Tricyclic Benzo[1,3]oxazinyl­oxazolidinones as Potent Antibacterial Agents with Excellent Pharmacokinetic Profiles against Drug-Resistant Pathogens

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.