Quinolone activity

Both levofloxacin and ciprofloxacin are quinolones active against both Gramnegative and Gram-positive bacteria. However, levofloxacin has greater activity against pneumoccocci than ciprofloxacin. Levofloxacin may cause tremor and tachycardia as side-effects. All quinolones should be administered with caution in patients with a history of epilepsy. 

The quinolones have long enjoyed a favorable pharmacokinetic profile. They are well absorbed and distributed in body tissues and fluids. A typical dose is between 100 mg and 1 g. The older agents have half-lives under 3 h, but a more typical value is between 4 and 14 h. Protein binding tends to be low to moderate (15-65%), but there are some exceptions such as nahdixic acid (90%) and garenoxacin (80%) (Howe and MacGowan, 2004). Bioavailability ranges from 55 to 100% (Dudley, 2003b). It has been well estabhshed in the hterature that the effectiveness of quinolones can be dramatically reduced if the medication is taken with an antacid. Many antacids are salts of divalent and trivalent cations such as Al " , Ca, and Mg " ". In addition, Fe " , Cu " , Ni " ", Zn " ", and also reduce quinolone activity. All these cations form a chelate with... 

Quinolones and fluoroquinolones are widely used against bacteria and mycobacteria [108], Recently, it has been shown that, similarly to T. gondii, at pharmalogical concentrations, ciprofloxacin (Fig. 18) acts on P. falciparum [109]. Among all the (fluoro)quinolones active on bacteria and tested against P. falciparum strains (3D7 or NF54-R), none of them showed an activity better than 1 pg/mL (the most... 

Another important development in the stmcture—activity relationships of quinolone antibacterials came with the introduction of the 1,8-bridged quinolone ofloxacin (6a). In this quinolone, the movement of the ethyl group at the 1-position is restricted by "tying" it to the 8-position in the form of a 1,4-benzoxazine ring. In vitro activity improvements are found that are more or less comparable to the improvements noted with ciprofloxacin (35,41—43). 

When ofloxacin was first introduced it was made available as the racemate. Later the optical isomers were prepared and it was found that the (3)-enantiomer, DR 3355 (6b), was substantially more active (8—128-fold) than the (R)-isomer against a broad range of bacteria (47—50). This chiral preference is not unique to ofloxacin and has been demonstrated in other quinolones as well (51,52). This significant finding has already had an impact on the design of new quinolone antibacterials still in development (53). 

The 5-position of quinolones can be substituted by small groups such as halogens, hydroxyl, or amino (54—56). The amino group at this position can be advantageous, particularly when appHed to 6,8-difluoro-7-piperazinyl or 6,8-difluoro-7-pyrrohdinyl quinolones. In contrast to 6,8-difluoro quinolones, when this replacement is appHed to ofloxacin, the resulting derivative has reduced antibacterial activity (57). Replacement of the 5-amino group with methylamine or dimethylamine causes activity to drop substantially. Sparfloxacin [110871-86-8] (21), a representative of 5-amino-6,8-difluoro quinolones, affords modest improvements in gram-positive activity as well as increased in vivo potency when compared with both ciprofloxacin and ofloxacin (54). 

The 8-position of the quinolone nucleus can often be advantageously substituted by fluorine (58) or chlorine (59) to give compounds with improved antibacterial potency over hydrogen in this position. With 1,8-naphthyridines, activity is reported to be approximately equivalent to the quinolone bearing a hydrogen in this position (60). As an example of this, see the data for norfloxacin (8) and enoxacin (7) in Table 2. 

A surprising development involving the 3-position has been presented (61,62). This position traditionally has had a carboxylic acid group and attempts to replace the carboxylate have resulted in lower antibacterial activity. However, it was demonstrated that the carboxylate could be replaced with an isothiazolo ring fused between the 2- and 3-position of the quinolone nucleus. A-62824 [111279-87-9] (22), illustrates this stmctural modification as apphed to ciprofloxacin. 

Another interesting approach to obtaining potent, broad-spectmm activity has been reported (127). The "dual-action" antibacterial concept involves incorporation of two moieties having complimentary antibacterial modes of action into the same molecule, and uses the mode of action of one part to release the second antibacterial at the site of action. This approach is exemplified in Ro 23—9424 (47) (127), which uses the mode of action and reactivity of the cephalosporin moiety (Fig. 2) to release the quinolone portion. 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

The generally accepted structure-activity relationships developed in the early work in the quinolone series held that the N-1 substituent needed to be small and aliphatic. This picture was upset in a dramatic way with the discovery of the excellent potency and antimicrobial spectrum of difloxacin (45) and its congeners in which the substituent on N-1 is an aromatic ring. The synthe-... 

A fluorine atom in position 6 of the basic structure of quinolones enhances the antimicrobial activity considerably. All widely used quinolones are fluorinated in position 6 and the term fluoroquinolones is often used to describe these drugs. However, some new quinolones with similar antimicrobial activity are not fluorinated in position 6 (e.g. garenoxacin, PGE9262932) and therefore the term quinolones is more appropriate to describe this group of antimicrobial agents. 

A kinetic study of the deuteration of pyridones and quinolones by deuterated sulphuric acid yielded the data in Table 148sl0. For the 4-pyridones, the rapid rise in rate with increasing acidity in strongly basic solutions, and the levelling off in rate at about H0 = 0 is consistent with reaction on the free base as is the small negative entropy of activation. The similarity in rate between 4-pyridone and its 1-methyl derivative shows reaction to take place on the form (XII) and not (XIII), viz. 

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). 

Chromosome function Quinolones Metronidazole (also ) Nitrofu rantoin Rifampicin (also ) 5-Fluorocytosine Inhibit DNA gyrase DNA strand breakage DNA strand breakage Inhibits RNA polymerase Inhibits DNA synthesis No action on mammalian equivalent Requires anaerobic conditions not present in mammalian cells No action on mammalian equivalent Converted to active form in fungi... 

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) ... 

A series of l-cyclopropyl-6,8-difluoro-l,4-dihydro-7-(2,6-dimethyl-4-pyri-dinyl)-4-substituted-quinolones (XIX) was synthesized by Kuo et al. [72] and their inhibitory activities against topo II evaluated. Using their data, we developed Eq. 20 (Table 16) ... 

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