- Studies on Anti-MRSA parenteral cephalosporins I. Synthesis and antibacterial activity of 7
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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)-hydroxyimino 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 activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo [1,2-b]pyridazinium-1-yl) methyl-7β-[2-(5-amino -1,2,4-thiadiazol-3-yl) -2(Z)-hydroxyiminoacetamidol]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.
- Ishikawa,Iizawa,Okonogi,Miyake
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p. 1053 - 1070
(2007/10/03)
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- Synthetic studies on condensed-azole derivatives. IV. Synthesis and anti-asthmatic activities of ω-sulfamoylalkyloxyimidazo[1,2-b]pyridazines
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A series of novel (imidazo[1,2-b]pyridazin-6-yl)oxyalkylsulfonamides was synthesized and evaluated for the ability to inhibit platelet activating factor (PAF)-induced bronchoconstriction in guinea pigs. The compounds bearing a gem-dialkyl or a cycloalkylidene group at the 2 position of the sulfamoylpropyloxy group in the side chain were found to have potent activity. Among them, 3-(imidazo[1,2-b]pyridazin-6-yl)oxy-2,2-dimethylpropanesulfonamide (6) showed excellent anti-asthmatic activity and the longest duration of action. The compounds bearing a methyl group at the 7 or 8 position of the imidazo[1,2-b]pyridazine ring were found to have enhanced activity. Among them, 3-(7-methylimidazo[1,2-b]pyridazin-6-yl)oxy-2,2-dimethylpropanesulfonamide (25) showed the most potent inhibitory effect, and its anti-asthmatic effect in an experimental model of allergic asthma was superior to that of theophylline. The structure-activity relationships in this series of compounds are discussed.
- Kuwahara, Masaaki,Kawano, Yasuhiko,Shimazu, Hiroshi,Ashida, Yasuko,Miyake, Akio
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p. 122 - 131
(2007/10/03)
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