Nalidixic acid, structure

Nalidixic acid is stable up to five years under reasonable conditions of temperature and humidity. Pawelczyk and Plotkowiakowa(17) subjected sodium nalidixate solutions to accelerated aging, but were unable to identify decomposition products. Detzer and Huber(lS) studied the photolysis and thermolysis of nalidixic acid in the presence of oxygen. Photolysis produced de-carboxylated nalidixic acid, structure A, and a diketone product, structure B, as well as carbon dioxide and ethylamine. 

Quantitative Structure—Activity Relationships of Antibacterial Compounds Based on the Nalidixic Acid Structure... 

Over 120 compounds based on the nalidixic acid structure were subjected to QSAR analysis against one Gram-positive and two Gram-negative bacteria. Somewhat inconsistent results were obtained, probably due to two responses being required before significant inhibition of bacterial growth is observed. 

BLOCK ET AL. Antibacterial Compounds and Nalidixic Acid Structure 311... 

BLOCKETAL. Antibacterial Compowtds and Nalidixic Acid Structure 321... 

Since the introduction of nalidixic acid in 1963, structural modifications on the quinolones have been performed to improve either the antibacterial efficacy or pharmacokinetic/toxicologic profiles of these compounds. The newest quinolones possess broad-spectrum activity, favorable pharmacokinetic/toxicologic profiles, and potency against bacterial strains that are resistant to older generations of quinolones. This section describes the synthetic procedures for the new generation of quinolones that were studied during the 1995-2005 period. 

Figure 5 shows the ultraviolet spectra of nalidixic acid at about 7.5 mcg/ml in 0.1 N NaOH, methanol, and chloroform, obtained on a Perkin-Elmer 323 recording spectrophotometer. The intensity, position, and fine structure present in each spectrum is related to the solvent polarity. These spectra are in agreement with the spectra published by Salim and Shupe.(2) Zubenko and Shcherba also report that there are two bands in methanol and 0.1 IJ NaOH, at 258 nm and 324 or 332 nm, respectively.(5) Gafari( ) has reported three bands in methanol 213-216 nm (lLa), 255 nm (lLb) and 320-322 nm (oc). Gafari also reports an absorbance in 0.1 II NaOH at 279-281 nm and 325 nm. These wavelengths are about 3-10 nm lower than those reported by other sources.(2)(5)(7)... 

Quinolones are synthetic compounds designed around nalidixic acid, a naphthyridine derivative used to treat urinary tract infections in the 1960s. By replacing various functional groups within the nalidixic acid pharmacophore with bioistosteric substitutions, three structural classes of quinolones were devised ... 

Many compounds will undergo dimerization reactions those containing thiols (e.g., disulfide formation) olefins, alcohols, and carboxylic acids (or other carbonyl chemistry e.g., aldol condensation reactions). Indoles have been shown to dimerize under acidic conditions. The dimerization is presumed to occur as shown in Figure 120 via protonation at C3 and nucleophilic attack of a second indole on C2. Phenols have been shown to dimerize under free radical initiated oxidative conditions, usually to ortho phenols. Nalidixic acid API undergoes dimerization under thermolysis conditions to decarboxylate and produce a dimeric structure (Fig. 121) (172). 

Nalidixic acid, the first antibacterial quinolone (Figure 46-3), was introduced in 1963. It is not fluorinated and is excreted too rapidly to be useful for systemic infections. Oxolinic acid and cinoxacin are similar in structure and function to nalidixic acid. Their mechanism of action is the same as that of the fluoroquinolones. These agents were useful only for the treatment of urinary tract infections and are rarely used now, having been made obsolete by the more efficacious fluorinated quinolones. 

Accordingly, halogeno- 1,8-naphthyridines have proved to be valuable intermediates.427 Moreover, such naphthyridines (with structures broadly based on that of nalidixic acid and usually with fluoro substituents) have shown remarkable... 

Because of structural uncertainties and confusing nomenclature, much of the early literature is, frankly, of little more than historical interest. However, after 1930, when most authors adopted the present Chemical Abstracts naming (see Note on Nomenclature that follows), a reliable body of literature gradually accumulated on all six systems, albeit at very different rates. For example, data on the 1,8-naphthyridines greatly outnumbered those on the other systems, probably as a result of the discovery of significant antimicrobial properties associated with nalidixic acid as well as the intrinsic suitability of the 1,8-system for metal complexation. 

Introduction of the first fluorinated quinolone, norfloxacin [nor FLOX a sin], has been rapidly followed by new members of this class. These agents are totally synthetic and are closely related structurally to an earlier quinolone, nalidixic acid [nal i DIX ik]. The principal member of this group is ciprofloxacin [sip ro FLOX a sin], which has the widest clinical application. Other antibiotics in this group available in the United States are primarily employed to treat urinary infections (Figure 32.1). It seems likely that the size of this class of antibiotics will increase due to its wide antibacterial spectrum, favorable pharmacokinetic properties and relative lack of adverse reactions. Unfortunately, their overuse has already led to the emergence of resistant strains resulting in limitations to their clinical usefulness. 

The evolution of the quinolones, which began with nalidixic acid and has produced the modem fluoroquinones moxifloxacin, gatifloxacin and gemifloxacin, was based not only on modifications of the basic quinolone structure but also on the development of new cyclic amines for the 7-position. The cyclopropyl radical, which was introduced for the first time in ciprofloxacin, remains the most effective substituent for the 1-position. Moxifloxacin is an 8-methoxy fluoroquinolone with a novel enantiomerically pure S,S-2,8-diazabicyclo[4.3.0]non-8-yl radical in the 7-position. 

Nalidixic acid is an example of a clinically useful antibacterial agent, but oxolinic acid, which acts in the same way, is 10 times more potent. The structures of these two antibiotics are ... 

Quinolones are structurally related to nalidixic acid the names of fhe mosf recently introduced members of the group end in -oxacin, e.g. ciprofloxacin. They acf by preventing DNA replication. 

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