Basic design of beta-lactam antibiotics--cephalosporins.

ABSTRACT

Since the introduction of cephaloglycin and cephalothin as the first commercially available cephalosporin C derivatives, there has been a proliferation of new agents, predominantly injectables. These have provided compounds with increased potency, improved spectrum, and/or pharmacokinetic advantages. The nature of the modifications producing these changes is the subject of the present report. The pathway generally followed by chemists working on a nucleus suitable for modification is initially a combination of trial and error and application of analogies from related areas. Once a moiety conferring a desirable effect has been identified, it or its analogs will be widely utilized in an effort to achieve further improvements. The choice of derivatives to be made is appreciably influenced by potential patentability and the feasibility of synthesis. For oral cephalosporins, to achieve adequate intrinsic bioavailability, the 7 beta-side chain has almost invariably been found to require a primary amino group on the alpha-carbon (D-configuration). This has limited potential changes at the 7 beta-position and leaves the 3-position as the major site for introducing novel substituents. Among thousands of derivatives prepared, only a few have actually been developed for clinical use. For injectables, where oral absorption is not a factor, there are no such specific preferred entities for either the 3- or 7 beta-position. Because of this, cephalosporin derivatives containing a large and diverse group of substituents at these positions have been prepared. In addition, another substitution site was identified upon discovery of the cephamycins, antibiotics which differ from cephalosporins by the presence of a methoxy group at the 7 alpha-position. Substitution at this site confers remarkable beta-lactamase stability, but only methoxy has given acceptable potency. First generation injectables which have in the 3-position the naturally occurring acetoxymethyl group or other relatively simply substituents are very active against Gram-positive organisms and a few species of Gram-negatives. As new 3- and 7 beta-side chain moieties were studied, appropriate combinations yielded compounds active vs. a broader spectrum of Enterobacteriaceae and/or Pseudomonas aeruginosa or Bacteroides fragilis. Furthermore, dramatic changes in pharmacokinetics (longer half-lives) were achieved by both 3- and 7 beta-side chain modifications.(ABSTRACT TRUNCATED AT 400 WORDS)