Fluoroquinolones, formation

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. 

Photosensitivity is a common adverse effect of the fluoroquinolones. It results from an abnormal reaction of the skin to natural or artificial light sources, usually associated with the UVA part of the electromagnetic spectrum (315-400 nm), mediated by the absorption of light energy into fluoroquinolones, followed by degradation of the molecule and formation of cytotoxic photoproducts (64). 

Not fully understood. The quinolone antibacterials can form insoluble chelates with divalent ions, which reduces their absorption from the gut. Enteral feeds such as those used above contain at least two divalent ions, calcium and magnesium. However, an in vitro study found no evidence of chelate formation with fluoroquinolones and calcium or magnesium, and therefore suggested that either other divalent cations may be involved, or that the quinolones may be adsorbed onto other metal ions, proteins or fat in the enteral feed. ... 

One of their major classes of drugs, quinolone antibiotics, is associated with serious problems such as the syndrome of hemolysis. In some cases, uremia, coagulopathy, and hyperbilirubinemia were observed for fluoroquinolone antibiotics like temafloxacin. Other adverse reactions have also been reported on the central nervous system with symptoms of headaches, insomnia, and dizziness. Skeletal problems still remain theoretical for quinolones in the prenatal formation, but tendinitis and tendon rupture have occurred in small number of adult patients. " ... 

Scheme 19) (Sun et al., 2008). The characterization of a hydroxycarboxylic acid metabolite of trovafloxacin in preclinical species (Dalvie et al., 1996) lends further support for the metabolism of the cyclopropylamine ring in trovafloxacin to a reactive intermediate. The formation of the hydroxycarboxylic acid can occur from the addition of water to the a,(3-unsaturated aldehyde via Michael addition followed by oxidation as depicted for the model compound (Scheme 19). However, the proposal for reactive metabolite formation with trovafloxacin remains a speculation since the bioactivation studies did not involve the parent fluoroquinolone and no a,(3-unsaturated aldehyde or the corresponding glutathione conjugate has been detected in trovafloxacin incubations in human liver microsomes (Sun et al., 2008). Furthermore, the primary pathways of trovafloxacin clearance in humans include phase II metabolism (iV-acetylation, acyl glucuronidation, and iV-sulfation) (Scheme 19) with very minor contributions from phase I oxidative pathways (Dalvie et al., 1997). 

The determination of two fluoroquinolone antibacterials (ciprofloxacin and norfloxacin), either in pure form or in tablets, is possible on the basis of the formation of a ternary complex palladium(II)-eosin-fluoroquinolone in the presence of methyl cellulose as surfactant. The ternary complexes show an absorption maximum at 545 nm and obey Beer s law in the concentration range 3-10mgl for both quinolones. 

El-Brashy, A. M., Metwally, M. E. and El-Sepai, F. A. 2004. Spectrophotometiic determination of some fluoroquinolone antibacterials by binary complex formation with xanthene dyes. II Farmaco. 59 809-817. 

Unsubstituted4-fluoropyridine has been synthesized by reaction of 4-nitropyridine with Bn4NF at heating in DMSO [88]. Nucleophilic substitution of N02-group in quinolone 101 proceeds with use KF in DMSO at 140 °C (1.5 h) with formation substituted 4-fluoroquinolone 102 in 37 % yield [89] (Scheme 39). 

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. 

An effective way for introduction of a variety of heterocyclic fragments in the position 7 of the fluoroquinolone skeleton is the methodology of 1,3-dipolar cycloaddition reactions [164-167]. Indeed, the reaction of 7-azido derivative of 6-fluoroquinolone 39 with enamines of cyclic ketones and norbomene proceeds rather smoothly with the formation of the corresponding exo-l,2,3-triazolines 40 which undergo the cationic rearrangements into amidines 41 or aminonorbomane 42 [164, 165]. 7-Azido derivatives 39 are capable of reacting with heterocyclic amines to form new 7- fluoroquinolones (Scheme 20) [168]. 

One of the modem trend in the chemistry of fluoroquinolones is the formation of Pd(II) and Pt(II) complexes with a number of fluoroquinolones, such as ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin and gatifloxacin [375,376], Two examples are given below Scheme 62. 

---