Studies on anti-MRSA parenteral cephalosporins. IV. A novel water-soluble N-phosphono type prodrug for parenteral administration

Article abstract of DOI:10.7164/antibiotics.54.364

A systematic approach for improving the water-solubility of anti-MRSA (methicillin-resistant Staphylococcus aureus) cephalosporin derivatives is described. We first tried to improve the water-solubility of 7β-[2- (5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyimino-acetamido]- 3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]- 3-cephem-4-carboxylate (1a) by substitution of the C-3′ pharmacophore. Replacement of the C-3′ pharmacophore with a 1-methyl-4-pyridinio group improved the water-solubility without decreasing the anti-MRSA activity. Furthermore, we applied the N-modified prodrug strategy to the C-7 acyl group in order to enhance the water-solubility drastically. Among the compounds prepared, the N-phosphono type prodrugs 2a (1-methylimidazo [1,2-b]pyridazinium derivative) and 2b (1-methyl-4-pyridinio derivative) showed water-solubility appropriate for a product intended for intravenous injection and in vivo anti-MRSA activity comparable to that of vancomycin.