Piperazine Ciprofloxacin

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Other successful imprintings in pure methanol or methanol-water mixtures were observed with piperazine-based fluoroquinolones like, for instance, ciprofloxacin [79] and ofloxacin [80], respectively. In both cases, the functional monomer is MAA and the interaction is pH-dependent and due to strong ion pairs formed between the piperazine ring of the quinolones and the carboxylate group of MAA. 

The breakthrough in the development of quinolones came with the appearance of norfloxacin 6 [19], a second-generation quinolone which combined a 6-fluorine substituent with a piperazine ring in the 7-position of the basic compound. Additional quinolones then followed in rapid succession pefloxacin [20], enoxacin [21] and fleroxacin [22] (Fig. 14.5). Particular mention must be made of ciprofloxacin 8 [23-25], ofloxacin 5 [26,27] and its active enantiomer levofloxacin 7 [28]. These quinolones have a broad spectrum of activity, which also includes Gram-positive bacteria and Pseudomonas aeruginosa, as well as favorable pharmacokinetics. The rapid absorption of these compounds from the gastrointestinal tract and their effective tissue penetration also allows them to be used for the treatment of systemic infections. 

Chemical Structure C17H18FN3O3-HCl H2O. Ciprofloxacin has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position... 

The quinolone class of drugs were discovered in the 1960s when Lesher et al. isolated nalidixic acid as a by-product of chloroquine synthesis (2). More than a thousand quinolones and analogs have since been synthesized and evaluated in an attempt to reduce toxicity and increase antimicrobial potency. The attachment of a fluorine to C-6 and a piperazine or methylpiperazine to C-7 has led to more active agents such as norfloxacin, ciprofloxacin, ofloxacin and lomefloxacin (3). 

A lot of studies have been directed to the synthesis of fluoroquinolones, bearing a variety of piperazinyl substituents, since this part of quinolone molecule is of significant importance. Indeed, some representatives of 6-fluoroquinolones bearing at C(7) piperazine (norfloxacin, ciprofloxacin), 4-methylpiperazine (pefloxacin), 3-methylpiperazin (lomefloxacin, temafloxacin) proved to possess a much broader range of antibacterial activity, than those without the piperazine moiety, such as nalidixic and oxolinic acids. 

The difference in activity for R- and -enantiomers of 7-(3-methylpiperazin-l-yl)quinolones, obtained from the corresponding (R)- and (5)-f-butyl-2-methylpiperazin-l-carboxylates, proved to be in the range from 2 to 64 folds in 52 % of cases [95]. In order to improve transport through biological membranes the piperazine moiety in norfloxacin was modified considerably and compound 26 was obtained [96]. To clarify the mechanism of antibacterial action of fluoroquinolones at the cellular level, two regioisomeric citrate-functionalized derivatives of ciprofloxacin 27a,b [97] (Scheme 14) have been obtained and studied. 

Rather high antineoplastic activity of ciprofloxacin derivatives, containing a substituent in position 4 of the piperazine fragment has been shown [302], Elucidation of the structure-activity relationships for l-(2-thiazolyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridin-3-carboxylic acids has shown that several compounds of this series exhibit activity, comparable with the well-known drug etoposide [316-318], Also the data on activity of amides of 7-substituted l-(2-thia-zolyl)- and l-(2-benzothiazolyl)-l,8-naphthyridin-4-on-3-carboxylic acids have been reported [319], Ethyl l-(4-cyano-2,3,5,6-tetrafluorophenyl)-6,7,8-trifluoro-4-oxo-l,4-dihydroquinolin-3-carboxylate proved to inhibit the phosphorylation process of transcription STAT3 activator that plays an important role for cancer therapy [320],... 

The fluorinated quinolones are generally more potent and less toxic than the first-generation agents. Agents containing a piperazine group at the C-7 position, such as ciprofloxacin and norfloxacin, are useiul in the treatment of pseudomonal infections. The fluoroquinolones inhibit bacterial topoisomerase II (predominantly) and topoisomerase IV. 

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