Studies on anti-MRSA parenteral cephalosporins - I. Synthesis and antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyiminoacetamido]-3-(substituted imidazo[1,2-b]-pyridazinium-1-yl)methyl-3-cephem-4-carboxylates and related compounds

In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyi mino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1,2 -b]pyridazinium or 5-substituted imidazo[1,2-a]pyridinium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activ ity of CZOP two to eight times, a slight decrease in the activity against G ram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1,a-b]pyridazinium-1-yl)methyl-7 b eta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)hydroxyimilzoacetamido]-3-cephem -4-carboxylate (44a) showed an excellent balance of activity against MRSA a nd Gram-negative bacteria.