title: Synthesis and antibacterial activity of new tetracyclic quinolone antibacterials.
abstract: A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.
authors.affiliation: New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Taguchi
authors.forename: H
authors.initials: H
authors.lastname: Kondo
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Kawahata
authors.forename: Y
authors.initials: Y
authors.lastname: Jinbo
authors.forename: F
authors.initials: F
authors.lastname: Sakamoto
authors.forename: G
authors.initials: G
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D004926:Escherichia coli; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D015363:Quinolones