Fluorocyclopropyl quinolones. 1. Synthesis and structure-activity relationships of 1-(2-fluorocyclopropyl)-3-pyridonecarboxylic acid antibacterial agents.
A series of 1-(2-fluorocyclopropyl)-3-pyridonecarboxylic acids has been prepared. These derivatives are characterized by having a fluorine atom at the 2-position on the cyclopropane ring as the N1 substituent and consist of both cis and trans stereoisomers. Structure-activity relationship studies indicate that the cis derivatives are more potent against Gram-positive bacteria than the corresponding trans counterparts, but the difference in potency against most Gram-negative bacteria is much smaller. The inhibitory effect of compounds 4, 5, 26, 27, 38, and 39 on supercoiling activity of DNA gyrase obtained from E. coli KL-16 correlated with their MICs against the same strain and also depend on their (26, 27, 38, 39) stereochemistry. Introduction of a fluorine atom on the cyclopropyl group resulted in the reduction of lipophilicity compared with the corresponding nonfluorinated quinolones.
Atarashi
S
S
Research Institute, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
Imamura
M
M
Kimura
Y
Y
Yoshida
A
A
Hayakawa
I
I
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D024841:Fluoroquinolones; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D002264:Carboxylic Acids; D024841:Fluoroquinolones; D015363:Quinolones