Quinolones derivatives

Nitrokerene dithiodceral reacts with anthrarulic esters to afford quinolone derivatives, which are converted into diazepinones by reductive cyclizadon The review by Kolb cavers synthetic apphcadon of nitroketene chthioacetM for heterocychc compounds Csee Scheme 10 26 ... 

The term quinolone antibacterials describes a large group of drugs that are 4-quinolone derivatives with a... 

Eissenstat et al. [71] synthesized a series of quinolone derivatives (XVIII) and evaluated their inhibitory activities against topo II. From their data Eq. 19 was derived (Table 15) ... 

The quinolone derivative that is most effective against Pseudomonas aeruginosa is... 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

Witkop and Goodwyn reported (288) that ozonolysis of yohimbine (74) and its derivatives led to the corresponding quinolone derivatives. This reaction has been thoroughly investigated by Winterfeldt (289). For example, autooxidation of lactam 347 resulted in quinolone 599, which upon treatment with phosphoryl chloride, followed by catalytic reduction, gave pyrrolo[3,4-h]quioline derivative 600 (290). This transformation was also used as a key step in the biomimetic synthesis of camptothecin (601), performed by Winterfeldt et al. (291, 292). 

A-56620) and (21 c) (difloxacin) were compared with the corresponding 1 -ethyl derivatives, norfloxacin and pefloxacin in mouse protection tests versus E. coli Juhl (Table 6.8). The two 7-(4-methylpiperazin-l-yl)quinolone derivatives, difloxacin and pefloxacin show enhanced oral activity relative to the 7-(piperazin-l-yl)quinolones, A-56620 and norfloxacin, respectively the absolute improvement in ED50 values in the 1-phenyl series is less dramatic. However, it should be noted that difloxacin, the more active agent in vivo, is 2 log2 dilutions less active in vitro. 

As an extension of this work, Atkinson and co-workers (123) prepared l-dibenzylamino-l,2-dihydro-2-quinolone (78) and 1 -(/V-benzy l-N-carboxy-methyl)amino-l, 2-dihydro-2-quinolone (79). The benzylic protons of 78 showed an AB quartet that did not coalesce up to 180°C, and 79 was resolved into optical isomers. The E, for racemization was 26.2 0.4 kcal/mol. Various attempts were made to elucidate the possible pathways for isomerization in these quinolone derivatives (123). Radical dissociation, a sigmatropic shift followed by rotation, and restricted rotation about the S—N bond were excluded. The aforementioned authors (123) also excluded the possibility of nitrogen inversion and preferred restricted rotation about the N—N bond as an explanation for the existence of stereoisomers. They supported this explanation by examining the steric effects... 

WIN 57294 137 is a potent inhibitor of DNA gyrase it is both clastogenic and mutagenic, which precluded its development as a human anti-infective agent [193]. This compound was subsequently found to possess moderate topo II inhibitory activity ( 50=7.6 pM). Structure activity relationship studies of WIN 57294 137 resulted in the discovery that the 3-CO2H group was not a requisite for topo II potency for 138, ( 50= 17 pM) [194]. A conformationally rigid quinolone derivative 139 has been reported to display better topo II potency ( 50=2.77 pM) [195]. 

Norfloxacin Norfloxacin, l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolincarboxylic acid (33.2.18), is the first representative of a series of fluorinated qninolones as well as the first drug of the quinolone derivatives used in medicine that contains a piperazine snbstituent. The method of synthesis is basically the same as that suggested for synthesizing nalidixic and oxolinic acids. 

Cross-resistance between nalidixic acid and other quinolone derivatives (eg, oxolinic... 

It is 4-quinolone derivative effective against gram negative bacteria mainly . coli and Shigella. It is less effective against Klebsiella and Aerobacter species and very... 

Although hundreds of different quinolone derivatives have been synthesized, only buquinolate, decoquinate, and methylbenzoquate have shown good efficacy against all species of chicken coccidia (Fig. 5.5). Their activity is essential coccidi-ostatic against the invading sporozoites as a result, if treatment is delayed after animals have become infected, anticoccidial activity is not effective. All quinolones are virtually insoluble in water and very poorly absorbed and, as a consequence, are nontoxic and result in low residue levels in the tissues of treated animals. 

Fig. 5.5 Chemical structures of commonly used quinolone derivatives.

Decoquinate is another quinolone derivative also incorporated in the feed. It is administered at a level of 20-40 ppm in the feed continuously for prevention of coccidiosis in broiler chickens, at 100 ppm for 28 days for prevention of coccidiosis in ewes and lambs, and at 500 ppm for at least 28 days for prevention of coccidiosis in cattle. Many feedlot farmers also use a 28 day feeding program for all incoming cattle to guard against costly disease that can destroy a feedlot. It is an approved feed additive in Europe, as defined by Directive 70/524/EEC (47). 

Metliylbenzoquate is probably the most potent among the anticoccidial quinolone derivatives. It is often used at 8.35 ppm in the feed in conjunction with other coccidiostats, especially clopidol, for prophylaxis of coccidiosis in chickens and turkeys. 

Chemists at Pfizer have developed short routes to novel tricyclic quinolone derivatives of interest as potential antibacterials. The overall transformation is illustrated by 1 - 2. 

In the reaction of the isatins 7 [154, 155], 54 [17, 154, 155], or 186 [155, 158, 159] with malonic acid in the presence of sodium acetate [155, 158] or in acetic acid [17, 154, 155, 159] the reaction products were 2-hydroxy-4-quinolinecarboxylic acids, which usually exist in the form of the 2-quinolone derivatives 187, as a result of decarboxylation of the initially formed dicarboxylic acids. Compound 187 with R = R1 = R2 = H and R3 = Me was patented as a plant growth regulator (Aureorysin) [158],... 

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