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 bee n prepared. These derivatives are characterized by having a fluorine a tom at the 2-position on the cyclopropane ring as the Nl substituent a nd consist of both cis and trans stereoisomers. Structure-activity rel ationship studies indicate that the cis derivatives are more potent ag ainst Gram-positive bacteria than the corresponding trans counterparts , but the difference in potency against most Grain-negative bacteria i s much smaller. The inhibitory effect of compounds 4, 5, 26, 27, 38, a nd 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 lipophilici ty compared with the corresponding nonfluorinated quinolones.