Studies on Anti-MRSA Parenteral Cephalosporins III. Synthesis and Antibacterial Activity of 7β-[2-(5-Amino-l, 2, 4-thiadiazol-3-yl)-2(Z)- alkoxyiminoacetamido]-3-[(E)-2-(l-aIkylimidazo[l, 2-b]pyridazmium-6-yI)thiovinyI]- 3-cephem-4-carboxylates and Related Compounds

Abstract

In the course of our exploration for a novel cephalosporin derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we modified the C-3 linked spacers of cephem derivatives bearing a l-methylimidazo[l, 2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetyl group at the C-7 position. The optimal spacers were the (E)-2-vinyl and (E)-2-thiovinyl groups seen in 19a and 29aa, respectively. Their anti-MRSA activity was 16 to 32 times as potent as that of cefozopran (CZOP). Focusing on the (E)-2-vinyl and (E)-2-thiovinyl spacers, we further modified the alkoxyimino groups in the C-7 acyl moiety and the 1-alkylimidazo[l, 2-b]pyridazinium moieties at the C-3' position and investigated the structureactivity relationships (SAR) of the derivatives. Consequently, we selected 7β-[2-(5-aminol, 2, 4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(l-methylimidazo[l, 2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (29ca) as a new anti-MRSA parenteral cephalosporin candidate for further biological evaluation. The selected 29ca showed anti-MRSA activity comparable to that of vancomycin (VCM) both in vitro and in vivo, high affinity (IC₅₀=2.7 μg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.