Orally active cephalosporins. I. Synthesis and structure-activity relationships of 7β-[2-(R)-amino-2-phenylacetamido]-3-(1H-1,2,3-triazol-4-yl)alkylthio methyl-3-cephem-4-carboxylic acid and related compounds

Abstract

The synthesis, antibacterial activity and oral absorbability of 7β-[2-(R)amino-2-phenylacetamido]-3-(1H-1,2,3-triazol-4-yl)methylthio methyl-3-cephem-4-carboxylic acid (1a) and related compounds (1b-p and 2) are described. The replacement of 1,2,3-triazole at the C-3 position of 1a with other heteroaromatics such as 1,2,4-triazole, imidazole and so on decreased its oral absorbability in mice (1b-j). the oral absorbability was also influenced by the spacer length between C-3 of cephem nucleus and C-4 of 1,2,3-triazole. The quantitative relationship between the bioavailability and the spacer length of cephalosporins (1a and 1k-p) is discussed. These results suggest that 1,2,3-triazole in the side chain at the C-3 position of cephems plays an important role in good oral absorption through its interaction with the transport system of small intestine.