New broad-spectrum cephalosporins with anti-pseudomonal activity. Iii. Synthesis and antibacterial activity of 7.Beta.- (D-2- (4-hydroxy-6-methylpyridine-3-carbonylamino) -2- (4-hydroxyphenyl) acetamido) -3- (methyl or substituted methyl) -ceph-3-em-4-carboxylic acids

Yamada, H.; Tobiki, H.; Jimpo, K.; Komatsu, T.; Okuda, T.; Noguchi, H.; Nakagome, T.

The Journal of Antibiotics 36(5): 543-551


DOI: 10.7164/antibiotics.36.543
Accession: 068516096

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The influence of various 3-substituents on the antibacterial activity of 7 beta-[D-2-(4-hydroxy-6-methylpyridine-3-carbonylamino)-2-(4-hydroxyphenyl) acetamido]ceph-3-em-4-carboxylic acids (III) was investigated. Introduction of an acidic substituent, such as a sulfo or a carboxyl group, to a 3-(1-methyl-1H-tetrazolyl)thiomethyl substituent (IIIf--i) resulted in a marked loss of activity against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, Escherichia coli, Klebsiella pneumoniae, and Enterobacter aerogenes, in contrast to an in crease of activity against Proteus mirabilis. Displacement of the acetoxy group of IIIb with pyridines (IIIm--p) enhanced the activity against P. aeruginosa and E. aerogenes: their activity against those strains were superior to that of the cephalosporin IIId having a 3-(1-methyl-1H-tetrazolyl)thiomethyl substituent. As a result of extensive studies in addition to the study of in vitro activity in this series, 7 beta-[D-2-(4-hydroxy-6-methylpyridine-3-carbonylamino)-2-(4-hydroxyphenyl) acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, code No. SM-1652, cefpiramide (generic name), was selected as a candidate for further biological and clinical investigations.