Synthesis and antibacterial activity of 1-oxacephem derivatives

A number of new optically active 1-oxacephem compounds were synthesized and tested for antibacterial activity. Various 7 alpha-unsubstituted 1-oxacephem nuclei 2a approximately 3 and a 7 alpha-methoxy-1-oxacephem nucleus 3, reported previously, were converted into the corresponding phenylacetylamino-, 2-thienylacetylamino-, D-mandelylamino-, D-phenylglycylamino-, and arylmalonylamino-1-oxacephem carboxylic acids. All the compounds except for the phenylglycylamine derivatives exhibited four-to sixteen-fold enhanced antibacterial activity compared with that of the corresponding cephalosporins. A combination of the 7 alpha-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-oxacephem nucleus and a 7 beta-arylmalonylamino side chain, as represented by compound 1 (disodium salt of 33), produced the highest efficacy among them: high antibacterial activity with a widely expanded spectrum against Gram-negative bacteria including resistant strains and Pseudomonas aeruginosa was observed.