Correlation between structure and biological properties of cephalosporins: the discovery of ceftriaxone

A research programme on cephalosporins was conducted in the author's laboratory with the aim of creating compounds with improved antibacterial and pharmacokinetic properties. In the first phase of this programme, great attention was paid to the study of how the structure of a 3-heterocyclic-thiomethyl side chain is capable of influencing antibiotic activity within a large series of model compounds possessing the same acyl side chain (2-thienylacetyl) as cephalothin. Several structural and physico-chemical features of the heterocyclic thiols used and the corresponding cephalosporins were correlated with in vitro and in vivo activity. As a result of these studies, the enolic 2-methyl-6-hydroxy-5-oxo-as-triazine-3-thiol was identified as the most interesting substituent, since the corresponding cephalosporin showed a valuable resistance breakthrough against several cephalothin-resistant Proteus strains. Consequently, further studies involving the use of different acyl side chains were performed. The introduction of the basic 2-(2-amino-4-thiazolyl)-2-(Z)-methoxyimino-acetyl side chain finally led to ceftriaxone, which has a very long elimination half-life of 8 hours, high beta-lactamase stability and extremely high chemotherapeutic efficacy against a broad spectrum of Gram-positive and Gram-negative pathogens. Owing to these properties, ceftriaxone is the first beta-lactam antibiotic suitable for once-daily administration.