7 alpha-formylamino substituent confers beta-lactamase-inactivating potency on 1-oxacephalosporins.

7 alpha-Formylamino-1-oxacephalosporins 7 alpha-formylamino-7 beta-[2- (methylaminocarbonyl)amino-2-(2-thienyl)acetamido]-3-[(1-methyl-1H -tetra zol-5-yl)thiomethyl]-1-oxa-3-cephem-4-carboxylic acid (F1) and 7 alpha-formylamino-7 beta-(2-[(4-ethyl-2,3-dioxopiperazine-1- yl)carbonylamino]-2-phenylacetamido)-3-[(1-methyl-1H-tetr azol-5-yl) thiomethyl]-1-oxa-3-cephem-4-carboxylic acid (F2) were stable against penicillinases and, moreover, inactivated cephalosporinases of Pseudomonas aeruginosa, Citrobacter freundii, and Enterobacter cloacae. Extensive studies of the inactivation of cephalosporinase of P. aeruginosa showed that it resulted from the formation of a transiently stable enzyme-compound complex. The 7 alpha-formylamino substituent was involved in the enzyme inactivation, because 7 alpha-methoxy congeners did not inactivate the enzyme. The number of compound molecules required for inhibition of an enzyme molecule was found to be 36 for F1 and 5.5 for F2, which suggests that the pathway to the complex formation branched off the hydrolysis pathway. Half-lives of the complexes were 400 min for F1 and 260 min for F2. 7 alpha-Formylamino compounds F1 and F2 had antibacterial activities similar to those of 7 alpha-methoxy congeners against beta-lactamase-producing gram-negative bacteria, whereas they were less active against non-beta-lactamase-producing strains of Escherichia coli and Staphylococcus aureus. The conclusion was that the 7 alpha-formylamino substituent conferred the ability to inactivate cephalosporinase on the 1-oxacephalosporins tested, without much impairment of their antibacterial activity.