STRUCTURE-ACTIVITY RELATIONSHIPS AND CRYSTAL STRUCTURES OF SOME INTERESTING OXAZOLIDINONES. William Watt,Fusen Han, John H. VanDrie, and Lisa M. Thomasco, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49007 USA

The oxazolidinones are a class of orally active, synthetic antibacterial agents being studied by investigators at Pharmacia and Upjohn. Their activity is potent against Gram-positive pathogens, such as staphylococcus and streptococcus, and Mycobacterium tuberculosis. At Pharmacia and Upjohn, we have two drug candidates, a piperazinyl fluorophenyl oxazolidinone and a morpholinyl fluorophenyl oxazolidinone and they are currently in Phase I human clinical trials.

We have determined some crystal structures of a few oxazolidinones in an attempt to understand their activity. The morpholinyl fluorophenyl oxazolidinone, U-100766, has been used as a model for structure activity relationships in order to develop other potential candidates. Through changing substituents on the aromatic ring and the effect of fluorine substitution, the biological activity differences have been pronounced. In addition, we have seen some interesting changes in conformation from these compounds.