Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part I: Synthesis and biological activities of 3-(benzothiazol-2-yl)thiocephalosporin derivatives, CP0467 and related compounds.

A series of cephalosporin derivatives with various bicyclic heterocycles at the C-3 position was synthesized and evaluated for antibacterial activity. Among them CP0467 (3a) showed excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) (MIC90 = 6.25 microg/mL), and extremely high affinity for the penicillin binding protein 2' of MRSA (I50 = 0.49 microg/mL). Furthermore, 3a showed a long-acting pharmacokinetic profile in mice (AUC(infinity) = 482.3 microg/h/mL and T(1/2) = 1.9 h).

In-vitro and in-vivo antimicrobial activities of a novel cephalosporin derivative, CP6162, possessing a dihydroxypyridone moiety at the C-3 side chain.

The antibacterial activity of a novel cephalosporin derivative, CP6162, possessing a dihydroxypyridone moiety at the C-3 side chain, was evaluated in vitro and in vivo, with ceftazidime, aztreonam and cefoperazone as the reference antibiotics. CP6162 showed weak or little activity against Gram-positive bacteria, but potent activity against clinical isolates of the Gram-negative species including strains of Pseudomonas aeruginosa, Ps. cepacia, Acinetobacter sp., Xanthomonas maltophilia, Serratia marcescens, Enterobacter cloacae and Citrobacter freundii, which were resistant to the reference antibiotics. The MICs of CP6162 were only slightly affected by the high producers of beta-lactamases except for cephalosporinase-producing C. freundii. It was, however, affected by the presence of ferric ion. CP6162 showed in-vivo activity paralleling the in-vitro activity, and also showed pharmacokinetic parameters similar to those of ceftazidime in mice and rats.