Design, Synthesis, and Structure–Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents

A series of novel benzoxazinyl-oxazolidinones bearing nonaromatic heterocycle or aryl groups were designed and synthesized. Their in vitro and in vivo antibacterial activities were investigated. Most of the (<b>3</b><i><b>S</b></i>, <b>3a</b><i><b>S</b></i>) biaryl benzoxazinyl-oxazolidinones exhibited potent activity against Gram-positive pathogens. SAR trends were observed; a pyridyl C ring was preferable to other 5- or 6-member aryl C rings, while fluorine substitution on the B ring generated derivatives with reduced activity. Various substituent group positions on the pyridyl ring were also evaluated. The resulting compounds displayed excellent activity against linezolid-resistant strains. Compound <b>45</b> exhibited excellent in vitro activity, with a MIC value of 0.25–0.5 μg/mL against MRSA and an activity against linezolid-resistant strains of 8–16-fold higher potency than linezolid. In a MRSA systemic infection model, compound <b>45</b> displayed an ED₅₀ < 5.0 mg/kg, a potency that is nearly 3-fold better than that of linezolid. This compound also showed excellent pharmacokinetic profiles, with a half-life of more than 5 h as well as an oral bioavailability of 81% in rats