Recent advances in oxazolidinones as antituberculosis agents.

Tuberculosis (TB) is an infectious and fatal disease caused by Mycobacterium tuberculosis (Mtb) and remains a serious public health threat; therefore, the development of new antitubercular agents is a priority for the World Health Organization's End TB strategy and the United Nations' Sustainable Development Goals to eradicate TB. Oxazolidinones are a class of synthetic antibacterial agents with a distinct mode of action developed for the treatment of Gram-positive bacterial infections. Many oxazolidinones exhibit good activity against Mtb, and some are currently in clinical trials for multidrug-resistant TB and extensively drug-resistant TB therapy. In this review, the mechanism of action, activity and toxicity of oxazolidinones and recent progress in the research and development of oxazolidinones as anti-TB agents are summarized.

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.

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.

Efficient and stereoselective one-pot synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones.

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic fused benzoxazinyl-oxazolidinones (20 examples) were obtained in good to excellent yields and high enantioselectivities with facile operation. Furthermore, four stereoisomers were afforded respectively in high ee values (>97.8%) via using different chiral 2,3-epoxy-4-trityloxybutanol. This methodology has been applied to the synthesis of key intermediates of drug candidates.