Norfloxacin, structure

According to molecular modeling studies, at the ground state the 6-lluoro analogue of 81 overlaps perfectly with the structure of norfloxacin (a well-established quinolone antibacterial agent) and is predicted to exhibit promising antibacterial activity. 

The synthesis and antibacterial properties of norfloxacin (2a) were described in 1980 [65]. In this key paper in the evolution of quinolone antibacterial agents, a series of 6,7,8-polysubstituted-l-ethyl-l,4-dihydro-4-oxoquinoline-3-carb-oxylic acids (13) was synthesized, employing previously developed quantitative structure-activity relationships (QSAR) for the corresponding 6-, 7- and 8-monosubstituted derivatives versus Escherichia coli. The QSAR analysis... 

A wide variety of organotin compounds developed by Carraher, Sabir, Roner, and others based on known antiviral drugs such as acyclovir and known antibacterial agents such as ciprofloxacin, norfloxacin, cephalexin (structure 11.21), and ampicillin inhibit a wide variety of viruses including ones responsible for many of the common colds, chicken pox, small pox, shingles, and herpes simplex. 

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. 

Animal studies show that the propensity to induce tendon lesions varies among fluoroquinolones. Fleroxacin, pefloxacin, levofloxacin, and ofloxacin were the most toxic, while enoxacin, norfloxacin, and ciprofloxacin had little or no effect (92). The structure of the substituent at... 

Co-administration of fenbufen and fluoroquinolones has been associated with seizures (141). The structure at the 7-position greatly affects the risk of NSAID-potentiated nervous system effects. Fluoroquinolones with unsubstituted piperazinyl rings (ciprofloxacin, enox-acin, and norfloxacin) have a strong interaction with NSAIDs (142). The increased risk of seizures is not caused by increased serum concentrations of fluoroquinolones, since their pharmacokinetics are not altered by NSAIDs (143). The mechanism has been suggested to be facilitation by fenbufen of the fluoroquinolone-induced inhibition of GABAa receptor function in the hippocampus and frontal cortex (144). 

This review will summarize the chemistry of the new fluoroquinolones. Norfloxacin, its first representative, was first reported in 1980 by H. Koga [3] and highlights structural modifications of the classical structures which have been reported in the scientific literature. 

Norfloxacin forms metal ion complexes with many di- and trivalent ions including Ca +, Mg +, Zn +, Fe " and Al + [28]. Formation constants for these complexes have been measured using potentiometric titrations between pH 2 and 11 (pATaS are 6.3 and 8.5 for the carboxylic acid and piperazinyl amine, respectively). Complexation occurs at the carbonyl-carboxylate site initially and subsequently at the piperazinyl amine as the pH increases, with these sites of interaction elucidated by single crystal structure determination [39-41]. At pH 6.5 the largest formation constant is found with AP+ and decreases according to the following trend Al + > Fe + Zn + > Mg + > Ca +. 

Y. Wang, L. Sun, W. Wang, and L. Yan, Crystal structure of norfloxacin methanol solvate Ci6Hi8FN3O3.CH3OH.H2O, Jiegou Huaxue, 24, 1359-1362 (2005). 

Fig. 6.17 Structures of some quinolones, a broad family of synthetic chemotherapeutic antibacterials based on the 4-quinolone (a) and 1,8-naphthyiidine (b) structures. Norfloxacin and nalidixic acid, respectively, are examples of a drug from each of these groups. Qnoxacin is an example of a quinolone antibacterial based on cinnoUne, an aromatic heterocyclic with two attached six-mem-bered tings containing adjacent nitrogens at positions one and two (d). The basic fluoroquinolone pharmacophore is shown in (c). The addition of a fluorine atom at position six of the two-ring nucleus produced a 100-fold increase in the antibacterial minimum inhibitory concentration...

The research led to the 6-fluoro structure 3, norfloxacin (Figure 2), which combined favorable antibaaerial properties and other characteristics. Depending on the organism, minimum inhibitory concentrations were improved up to 500-fold over nalidixic acid. The spectrum of activity was extended to Pseudomonas. This compound and the many other 6-fluoroquinolones diat have since reached the market have been successful in achieving clinical efficacy rates of about 90%. Norfloxacin is marketed in Japan, the United States, and other countries. 

Gao F, Yang P, Xie J, Wang H (1995) Norfloxacin metallocomplexes structure and antibacterial activity. J Inorg Chem 60 61-67... 

Figure 3 A few examples of marketed drugs that were discovered with the aid of computers. Norfloxacin is an antibiotic derived in a quantitative structure-activity study. Losartan is an antihypertensive agent that resulted from an extensive structure-activity study which obtained its initial direction from molecular modeling. Indinavir is an antiviral drug for treating autoimmune deficiency syndrome that was found with input from crystallography and molecular mechanics and molecular simulation calculations...

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