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The preparation and in vitro prolyl endopeptidase (PEP) inhibitory activity of a series of alpha-keto heterocyclic compounds is described. The design is based on the introduction of alpha-keto heterocycles at the C-terminal end of substrate-like peptides. Many of the compounds including those substituted with thiazole, benzothiazole, benzoxazole, imidazole, and pyridine groups exhibit IC50 potencies of PEP inhibition at nanomolar levels. Structure-activity studies of the C-terminal heterocyclic groups indicate the importance of an sp2 nitrogen atom at a beta-position from the adjoining ketone carbonyl group. This heterocyclic nitrogen atom would provide a critical hydrogen-bond interaction with the histidine residue of the catalytic triad in PEP. Our inhibitors would extend the generality of the alpha-keto heterocycle design to another serine protease.

The transformation is described of 3-formylcephem 1 into its oxime, substituted oximes, and substituted hydrazones and, thence, into the 3-cyano, 3-diazomethyl, and 3-oxonitrilomethyl derivatives. These reactive 1,3-dipoles undergo 1,3-dipolar cycloadditions with various dipolarophiles to give C-3 heterocyclic-substituted cephems.

The labile tert-butyldimethylsilyl esters of the azetidinones 6-8b served as the crucial synthons in the preparation of the potentially useful ylide pyridyl thio esters 18-20. These intermediates were utilized to synthesize a host of title carbapenems 25-30d, 32, and 49-53. The antimicrobial properties and DHP-I susceptibility of these carbapenems were studied with reference to thienamycin.

The total syntheses of the (+/-)-1-carba analogues of cefoxitin (11), 7 alpha-methoxydeacetylcephalothin (5) and cefamandole (31) and the (+/-)-1-oxa analogue of cefamandole (43) are described. Their bioactivity spectra against 14 typical organisms are similar to those of their natural 1-thia counterparts, with the 1-carba compounds somewhat less active and the 1-oxa compound more active than the natural ones.