Innovation and Development

A Novel Antibacterial Agent Identified

Dr. Yang Yushe’s group (the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS) has identified a series of novel benzoxazinyl – oxazolidinones bearing nonaromatic heterocycle or aryl groups. Their in vitro and in vivo antibacterial activities were investigated. Most of the (3S, 3aS) 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 45 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 45 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. The favorable in vitro and in vivo activities of compound 45, combined with its excellent PK profile, make compound it a very promising drug candidate. Evaluation of the safety of this drug candidate is currently under investigation (J. Med. Chem. 2011, 54, 7493–7502).