Fluorocyclopropyl quinolones. 1. Synthesis and structure-activity relationships of 1-(2-fluorocyclopropyl)-3-pyridonecarboxylic acid antibacterial agents

Abstract

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.

Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria

“…Thus, compound 5 showed a positive response, even though it has a combination of des-F(6) and the (1R,2S)-2-fluorocyclopropan-1-yl group at the N-1 position, which are reported to reduce genotoxicity. [23][24][25][26][27][28] The des-F(6) compounds 4, 6 and 8 showed negative responses as we expected. The results indicate the advantage of removing the fluorine atom at the C-6 position for reducing intravenous single-dose toxicity and micronuclei-forming toxicity.…”

“…[20][21][22][23] As a method to reduce this genotoxicity, we reported the usefulness of introducing a (1R,2S)-2-fluorocyclopropan-1-yl substituent into the N-1 position instead of a cyclopropyl substituent. [24][25][26] Furthermore, 8-methoxyquinolone derivatives were reported to exhibit potent antibacterial activity against Gram-positive bacteria and show reduced phototoxicity in comparison with several quinolone derivatives. 27 lone having the (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituent at the C-7 position (1, Fig.…”

Novel tactics for designing water-soluble molecules in drug discovery

“…This effect can be additive [41] except when F is added to the same carbon atom as in CF 3 . Examples from the drug discovery literature include the fluorination of the quinolone antibiotics 13 and 15, which yielded a -0.75 and -0.45 reduction in CHCl 3 /pH 7.4-buffer partitioning (K CHCl3/7.4 ) for 14 and 16 [42]. Likewise, the solubility of 17 at pH 6.5 and 7.4 was improved by twofold by replacing a single hydrogen with fluorine (18) [43].…”

Synthesis, antimycobacterial and antibacterial evaluation of l-[(1R, 2S)-2-fluorocyclopropyl]fluoroquinolone derivatives containing an oxime functional moiety

“…It is of concern that the central nervous system (CNS) toxicity of N1-cyclopropyl FQs with outstanding antibacterial activity has been pointed in the clinical field [14], the corresponding 2-fluorocyclopropyl counterparts could modulate the lipophilicity and reduce the CNS toxicity [15]. Sitafloxacin (STFX, Fig.…”