Semisynthetic cephalosporins. Synthesis and structure-activity relationships of analogues with 7-acyl groups derived from 2-(cyanomethylthio)acetic acid or 2-[(2,2,2-trifluoroethyl)thio]acetic acid and their sulfoxides and sulfones.
The synthesis and in vitro and in vivo activities of a series of cephalosporins having side chains derived from 2-[(2,2,2-trifluoroethyl)thio]acetic acid or 2-(cyanomethylthio)acetic acid and with acetoxymethyl or 3-heterocyclic thiomethyl substituents at the 3 position are described. In both series, increasing the oxidation state of the side-chain sulfur atom from sulfide to sulfoxide/sulfone decreased the in vitro gram-positive activity, but the effect on gram-negative activity was variable and less pronounced. The protective effectiveness in mice infected with Escherichia coli increased as the oxidation level of the side-chain sulfur was raised from sulfied to sulfoxide/sulfone. Replacement of the 3-acetoxymethyl by a 3-heterocyclic thiomethyl group resulted in overall improvement of activity both in vitro and in vivo for all oxidation states.
D000085:Acetates / Q000138:chemical synthesis; D000215:Acylation; D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004926:Escherichia coli / Q000254:growth & development; D005463:Fluoroacetates / Q000138:chemical synthesis; D051379:Mice; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis; D013454:Sulfoxides / Q000138:chemical synthesis
D000085:Acetates; D002511:Cephalosporins; D005463:Fluoroacetates; D013450:Sulfones; D013454:Sulfoxides