Synthesis and structure-activity relationships of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporin derivatives. II. Synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-7 alpha-methoxycephalosporins.

7 beta-[2-(2-Aminothiazol-4-yl)acetamido]-7 alpha-methoxycephalosporins were synthesized both by acylation of the 7 beta-amino-7 alpha-methoxycephalosporin compound (VIII) and a new direct acyl-exchange reaction of 7 alpha-methoxy-7 beta-phosphoramido compound (VII). Some of these compounds (IXa, IXb) showed higher antibacterial activity than the 7 alpha-unsubstituted compound against beta-lactamase-producing strains of Serratia marcescens and Proteus vulgaris.

Synthesis and structure-activity relationships of 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-cephalosporin derivatives. I. Synthesis and antibacterial activity of 7 beta-[2-alkyl- and 2-hydroxy-2-(2-aminothiazol-4-yl)-acetamido]cephalosporins.

2-Alkyl- and 2-hydroxy derivatives of 7 beta-[2-aminothiazol-4-yl)acetamido]cephalosporins were synthesized to improve the antibacterial activity of the parent compounds especially against beta-lactamase-producing organisms. Some of these compounds showed an increase in activity against Serratia marcescens (Xb, XXIIIa) and Enterobacter cloacae (Xb, XIV). The 2,2-dimethyl derivative (XXVIIIb) showed a definite loss of activity.

An approach to broad-spectrum cephalosporins.

Based on our view that cephalosporins with potent activities share active hydrogen(s) on the alpha-carbon of the side chain acyl, we undertook to introduce beta-ketoacid moieties onto the cephalosporin structure. Thus, starting with deacetylcephalosporin C (DCPC), first made available in quantities by our own fermentation technique, 7-amino-3'-O-acetoacetyldeacetylcephalosporanic acid (7-AACA) was made accesible. Acylation of 7-AACA with various beta-ketoacids followed by substitution at the 3'-position led to 7 beta-[2-(2-aminothiazol-4-yl)acetamido]-3-[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl]ceph-3-em-4-carboxylic acid (SCE-963, cefotiam), a potent broad-spectrum cephalosporin.