title: Synthesis and antibacterial activity of a new series of tetracyclic pyridone carboxylic acids.
abstract: A novel tetracyclic pyridone carboxylic acid with a thiazolidine ring, 1,2-dihydro-9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo -5H- thiazolo[3,2-a]quinoline-4-carboxylic acid (4a), and variants with a nitrogen atom (4b) or carbonyl group (4c) in the place of the 10-position oxygen atom of 4a were prepared and tested for antibacterial activity and inhibitory activity on DNA gyrase from Escherichia coli KL-16. The in vitro antibacterial potency with regard to the 10-position atom was found to be of the following order; O > NCH3 = C = O. The IC50 values for DNA gyrase inhibition activity for the 4a, 4b, and 4c compounds were 0.33, 0.53, and 0.67 g/mL, respectively. The activity of 4a, in which the C-3 methyl group and C-5 of ofloxacin (2a) were connected with a sulfur atom to restrict the conformation of 2a, was more potent than that of 2a against both Gram-positive and -negative bacteria, except for Pseudomonas aeruginosa. Compared to the tetracyclic pyridone carboxylic acid 1a, which has a flat thiazole ring, compound 4a showed comparable or slightly more potent activity against both Gram-positive and -negative bacteria, except for P. aeruginosa.
authors.affiliation: New Drug Research Laboratories, Kanebo, Ltd., Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Jinbo
authors.forename: M
authors.initials: M
authors.lastname: Taguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Kondo
authors.forename: T
authors.initials: T
authors.lastname: Miyasaka
authors.forename: H
authors.initials: H
authors.lastname: Tsujishita
authors.forename: F
authors.initials: F
authors.lastname: Sakamoto
authors.forename: G
authors.initials: G
authors.lastname: Tsukamoto
mesh_terms: D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II; D024841:Fluoroquinolones; D008826:Microbial Sensitivity Tests; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C083827:1,2-dihydro-9,1-(epoxymethano)-7-fluoro-8-(4-methyl-1-piperazinyl)-5-oxo-5H-thiazolo(3,2-a)quinoline-4-carboxylic acid; D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D011728:Pyridones; D015363:Quinolones; D004250:DNA Topoisomerases, Type II