Antibacterial fluoroquinolones

Dihalo-5-fluorobenzoic acids, obtained by oxidation of the corresponding acetophenones, have received considerable attention as intermediates for antibacterial fluoroquinolones [28, 29], In this regard, 1,2,4-trifluorobenzene reacts with acetyl chloride to give 2,4,5-trifluoroacetophenone [29] (equation 19) 1,3,5-Tn-fluorobenzene and 1,2-difluorobenzene yield 2,4,6-trifluoroacetophenone and 3,4-difluoroacetophenone, respectively [30] (equations 20 and 21). 

Morimura, T., Kohno, K., Nobuhara, Y., and Matsukura, H., 1997a, Photoreaction and active oxygen generation by photosensitization of a new antibacterial fluoroquinolone, orbi-floxacin, in the presence of chloride ion, Chem. Pharm. Bull. 45, 1828-1832. 

Morimura T, Ohno T, Matsukura H and Nobuhara Y, Degradation kinetics of the new antibacterial fluoroquinolone derivative, orbifloxacin, in aqueous solution, Chem. Pharm. Bull, 43,1052-1054 (1995). 

Abstract The data on 6-fluoro-l,4-dihydroquinolin-4-oxo-3-carboxylic acids and their structural analogues accumulated in the literature for the last 10-15 years are reviewed. Synthetic approaches to the quinolone system, as well as all kind of structural modifications by incorporating substituents into 1-8 positions or by means of annelation have been discussed. The structure-activity relationships for antibacterial fluoroquinolones, as well as the data on other types of biological activity for the family of bi- and polycyclic fluoroquinolones are presented. The formation of complexes of fluoroquinolones with metals and their applications have been considered. The bibliography - 377 references. 

Tetrafluorobenzene. This compouad has beea prepared by fluoriaatioa of hen2ene with cobalt trifluoride and subsequent combination of the dehydrofluoriaation and defluoriaation steps. Its ioni2ation potential is 9.01 V. Nitration gives 2,3,4,5-tetrafluoronitroben2ene [5580-79-0] ia 75% yield, an iatermediate to fluoroquinolone antibacterials (218). 

An illustration of a modified Wallach fluorination is the synthesis of 2 4 di chloro-5-fluorotoluene, an intermediate in the preparation of the fluoroquinolone antibacterial ciprofloxacin This was prepared in 69% overall yield by heating W(2,4-dichloro-5-methylphenyl) N, N dimethyltriazene in anhydrous hydrogen fluoride [44] (equation 11)... 

The Balz-Schiemann reaction continues to attract attention, with much of it generated by the interest in fluoroquinolones, e.g., (7), which is a potential antibacterial. Two approaches to its synthesis are possible—introduction of fluorine prior to or post ring construction. Decomposition of the tetrafluoroborate salt was unsuccessful, whereas the PF6 salt (8) gave only a poor yield (84JMC292). A more successful approach was the introduction of F into the pyridine nucleus prior to formation of the 1,8-naphthyridine ring (84JHC673). A comparison of decomposition media showed that cyclohexane was the best with regard to yield and time. 

Over 10000 quinolone antibacterial agents have now been synthesized. Nalidixic acid is regarded as the progenitor of the new quinolones. It has been used for several years as a clinically important drug in the treatment of urinary tract infections. Since its clinical introduction, other 4-quinolone antibacterials have been synthesized, some of which show considerably greater antibacterial potency. Furthermore, this means that many types of bacteria not susceptible to nahdixic acid therapy m be sensihve to the newer derivahves. The most important development was the introduction of a fluorine substituent at C-6, which led to a considerable increase in potency and spectrum of activity compared with nalidixic add. These second-generation quinolones are known as fluoroquinolones, examples of which are ciprofloxacin and norfloxacin (Fig. 5.19). 

The transformation of several fluoroquinolone antibacterials was examined and a number of products from ciprafloxacin were tentatively identified (Zhang and Huang 2005). The qninolone ring was nnchanged, and the major prodnct was produced by fission of the piperazine ring to an aniline. 

Zhang H, C-H Huang (2005) Oxidative transformation of fluoroquinolone antibacterial agents and structu-iraloly related amines by manganese dioxide. Environ Sci Technol 39 4474-4483. 

Flavonoids, physiological and nutritional aspects, 14 (1977) 285 Fluorescence-based assays, 43 (2005) 19 Fluoroquinolone antibacterial agents,... 

---