The Synthesis and In Vitro Testing Of Structurally Novel Isoxazolidine Antibacterial Agents Via an Acylnitroso Diels-Alder Reaction

The research in this dissertation focuses on the synthesis and in vitro testing of structurally novel antibacterial agents derived from acylnitroso Diels Alder adducts. The striking structural similarity of ?-lactam antibacterial agents to isoxazolidines derived from acylnitroso Diels Alder adducts led to the hypothesis that appropriately elaborated isoxazolidines might act as a ?-lactam surrogate. In order to test this hypothesis, several isoxazolidines were synthesized and tested against E. coli X-580, which is a stain of E. coli that is hypersensitive to ?-lactam antibacterial agents, and were found to have activity. In order to increase the potency and broad spectrum antibacterial activity, additional isoxazolidines were synthesized which incorporate side chains which are analogous to physiologically relevant side chains that many effective ?-lactam antibiotics have. These side chains included phenylglycine and amino thiazol methoxy oxime (ATMO). The current progress towards a diketopiperzine derived from an isoxazolidine is presented which could also exhibit antibacterial activity. The efforts towards an isoxazolidine containing an alcohol in the side chain are shown and the attachment of it to deferoxamine (DFO) which is a siderophore is proposed.