title: Chemical evolution of the fluoroquinolone antimicrobial agents.
abstract: In the past decade, significant progress has been made in understanding structure-function relationships of the new quinolones, which have a N-1-substituted, 1,4-dihydro-4-oxo-pyridine-3-carboxylic acid moiety as the basic nucleus. Modification of the groups affixed to positions C-6, C-7, and C-8 has made a major change in the antimicrobial activity, pharmacokinetic, and metabolic properties of the quinolones as have changes in the moieties affixed to the N-1 nitrogen. The new quinolones have a carboxyl group at position 3 and a keto group at C-4. The presence of a fluorine atom at C-6 enhances the deoxyribonucleic acid (DNA) gyrase inhibitory activity as well as the ability of the compounds to inhibit staphylococci. Position C-7 has been one of the most modified sites. Addition of a piperazinyl group markedly increased gram-positive activity, primarily antistaphylococcal activity; lowered the minimal inhibitory concentrations against Enterobacteriaceae, Haemophilus spp., and Neisseria spp.; and added activity against Pseudomonas aeruginosa compared with nalidixic acid. Methyl derivatives of the piperazine group or of the pyrroles have longer half-lives than do unsubstituted moieties. At the N-1 position, a cyclopropyl group appears to be most potent with respect to minimal inhibitory concentrations against Enterobacteriaceae and Pseudomonas. Ofloxacin is unique in that it has an oxygen substituted at C-8 with the substituent part of the ring system formed by fusion to the N-1 position. This has produced excellent in vitro activity against gram-positive species comparable with that of ciprofloxacin, excellent activity against the Enterobacteriaceae, and antipseudomonal activity superior to agents with an ethyl substitution at position N-1. The oxazine ring of ofloxacin provides excellent oral absorption with virtually 95 percent bioavailability; this modification also has prevented metabolism and has provided a long half-life of seven to eight hours.
authors.affiliation: Division of Infectious Disease, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
authors.forename: H C
authors.initials: HC
authors.lastname: Neu
mesh_terms: D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004755:Enterobacteriaceae / Q000187:drug effects; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013210:Staphylococcus / Q000187:drug effects; D013291:Streptococcus / Q000187:drug effects
chemical_list: D042462:4-Quinolones; D000890:Anti-Infective Agents; D004250:DNA Topoisomerases, Type II