Synthesis and structure-activity studies of antibacterial oxazolidinones containing dihydrothiopyran or dihydrothiazine C-rings.

A new series of antimicrobial oxazolidinones bearing unsaturated heterocyclic C-rings is described. Dihydrothiopyran derivatives were prepared from the saturated tetrahydrothiopyran sulfoxides via a Pummerer-rearrangement/elimination sequence. Two new synthetic approaches to the dihydrothiazine ring system were explored, the first involving a novel trifluoroacetylative-detrifluoroacetylative Pummerer-type reaction sequence and the second involving direct dehydrogenation of tetrahydrothiopyran S,S-dioxide intermediates. Final analogs such as 4 and 13 represent oxidized congeners of recent pre-clinical and clinical oxazolidinones.

Recent developments in the identification of novel oxazolidinone antibacterial agents.

The oxazolidinones are a promising new class of synthetic antibacterial agents. Here, we review recent efforts directed at the discovery of new antibacterial compounds of this class. New structures and structure-activity relationships (SAR) are discussed in the context of earlier work in the field. Key issues of potency, spectrum, selectivity, in vivo efficacy, and pharmacokinetic profile of the new analogs are addressed.

Novel oxazolidinone-quinolone hybrid antimicrobials.

Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and evaluated. Representative analogues 2, 5, and 6 display an improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new antimicrobials is consistent with a combination of protein synthesis and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism.