Chemical Properties

Aqueous Solubility

Fluoroquinolones as a class are generally fairly insoluble in water. All modern quinolone agents are zwitterionic in character, due to the presence of both a carboxylic acid and a basic amine; pKa values for these functional groups have been reported as 5.5-6.3 for the carboxylic acid and 7.6-9.3 for the distal amino group [134]. At low pH, both the amine and the carboxylic acid are protonated, giving the molecule an overall positive charge. Conversely, at high pH the amine is in the free base form, while the carboxyl group exists as the carboxylate anion, providing a net negative charge. Because of this, quinolones tend to be more soluble in water at acidic and basic pH, with minimum solubility expressed at neutral (physiological) pH values [135]. The crystal packing of quinolones, in which the aromatic nuclei are stacked [74], also contributes to lowered aqueous solubility; this class of agents is characterized by very high melting points, generally >200°C, indicating that the crystal forms are very stable. Extremely low solubility has been measured [136] for some quinolone agents; tosufloxacin, for example, exhibits a water solubility of 0.008 mg/ml at physiological pH [136].

The extent of aqueous solubility becomes particularly important for intravenous administration of quinolone agents. Of the more recent quinolones, an intravenous dosage form has been developed using the parent drug for ciproflox-acin, ofloxacin, fleroxacin, clinafloxacin, levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, and pazufloxacin. In cases where the intrinsic solubility of quinolones is low, prodrug strategies have been employed. The intravenous formulation for trovafloxacin consists of the highly soluble dipeptide derivative alatrofloxacin (Figure 8), which is hydrolyzed in vivo to provide the parent drug [137].

Chelation of Divalent and Trivalent Metal Cations

The well-known effects of antacids and certain mineral supplements in decreasing absorption and bioavailability of fluoroquinolones [138] can be traced to the P-keto-carboxylic acid functionality common to all quinolones (see Figure 1). Through the use of techniques such as infrared spectroscopy and 19F and 13C nuclear magnetic resonance spectroscopy, these groups have been shown to chelate divalent and trivalent metal ions [139,140]. These chemical analyses are supported by in vivo studies showing that concurrent administration of aluminum hydroxide affects the absorption of neither a quinolone analogue lacking the carboxylic acid group [122] nor a prodrug of ofloxacin in which the carboxylic acid is masked [141]. The strength of chelation to a quinolone varies with the metal ion, with affinity constants rising in the order Ca2+ < Mg2+ < Fe3+ < Al3+ [142]. For a collection of quinolone agents, it was shown that there is a correlation between the stability constants of the quinolone-aluminum chelates and the diminution in AUC on aluminum coadministration. Two 5-amino quinolones were outliers in this analysis, suggesting that the chelate structure may be affected by the presence of a 5-substituent [122]. That the C-4 carbonyl group can interact with a 5-amino group was evidenced by the fact that the intramolecular hydrogen bond between the C-4 carbonyl oxygen and the acidic proton on the C-3 carboxylic acid in sparfloxacin is weaker than the corresponding hydrogen bond in the 5-unsubstituted pefloxacin [139]. In accord with these data, sparfloxacin has been shown to suffer less disruption of absorption on antacid coadministration than other quinolone agents [122].

The decrease in absorption of quinolones in the presence of cations is often attributed to the lower solubility of chelates in the intestinal tract. A mechanistic study [143] of the interaction of levofloxacin with aluminum hydroxide suggested that quinolones may adsorb onto aluminum hydroxide that has reprecipitated in the small intestine due to the higher pH at that site as compared to gastric fluid. It has been found in the laboratory [144] that many chelates are actually more soluble than the parent quinolones, leading to the suggestion [145] that the decrease in lipophilicity that occurs on metal chelation may be an important factor that leads to reduced bioavailability. A different effect has been invoked to explain the decrease in antibacterial activity of quinolones in the presence of high levels of magnesium ions (see the section on "Magnesium Levels").


The chemical concept of stereochemistry has become of increasing importance in making decisions regarding the advancement of agents that can exist as isomers. The three-dimensional nature of drugs and the potential for arraying four different substituents on a single carbon in two nonsuperimposable ways result in the existence of stereoisomers for any quinolone agent that has a chiral center (a carbon with four different substituents in a molecule with no mirror plane, such as ofloxacin) or substituents in different positions on a saturated ring (as in sparfloxacin).

Earlier quinolones such as flumequine, ofloxacin, and lomefloxacin were developed as racemates (1:1 mixtures of the mirror images), as are a number of the more recent agents (such as tosufloxacin, grepafloxacin, clinafloxacin, gemifloxacin, and gatifloxacin). It has been found, however, particularly for chiral centers close to the quinolone nucleus, such as the methyl group on the pyridobenzoxazine nucleus of ofloxacin, that the orientation of the substituent can be of critical importance to the compound's antibacterial activity. The (5)-methyl derivative levofloxacin, where the methyl group is designated as coming up above the plane of the page, is from 8- to 128-fold as potent as the (R)-methyl enantiomer in vitro, and twice as active as the racemate ofloxacin [146]. Similarly, pazuflox-acin is up to 256-fold more potent than its (R) enantiomer [133]. In the case of levofloxacin, an advantage was also obtained as regards aqueous solubility, as levofloxacin was found [147] to be 10-fold more soluble in water than the racemate ofloxacin.

Although the presence or absence of the fluorine on the N-1 cyclopropane did not greatly affect the potency of sitafloxacin [148], the stereochemistry of the fluorine on a closely related series was found to be important. The cis orientation of nitrogen and fluorine about the cyclopropane provided more potent Gram-positive activity than did the trans isomer. The effect on Gram-negative activity was much smaller [149]. For the four cis-fluoro isomers of sitafloxacin itself (the different combinations of enantiomers at the N-1 cyclopropane and at the C-7 aminopyrrolidine), the indicated absolute stereochemistry provided the most potent Gram-positive and Gram-negative activity [105]. More recently, this heightened activity was shown to be mediated at the enzyme level, with sitafloxacin exhibiting more potent activity than its stereoisomers against E. coli gyrase and S. aureus topoisomerase IV [27].

Chiral centers at C-7 that are at some distance from the quinolone nucleus often contribute less significantly to biological activity. The enantiomers of temaflox-acin [150], tosufloxacin [151], moxifloxacin [152], and gemifloxacin [153], for instance, were found to be nearly equipotent. As mentioned previously, however (see the section on "Selectivity"), the relative orientation of the methyl groups on the C-7 piperazine of sparfloxacin is important for enzyme selectivity.

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