Structural and historical background

Quinolone antibacterial research and development has enjoyed an enormous worldwide effort since the early 1960s. During this time, more than 10,000 structurally related agents have been described in many hundreds of patents and journal articles. The product of this wealth of research has been a continually improving progression of marketed quinolone antibacterial agents. From the early days of Gram-negative-selective agents limited to treatment of urinary tract infection, the field has matured to provide broad-spectrum drugs capable of treating not only urinary tract infections but also systemic infections caused by Gram-positive and Gram-negative pathogens at sites ranging from skin to joints to the respiratory tract. Some newer agents incorporate activity against anaerobic pathogens, making them useful in surgical and gynecological infections. The pharmacokinetic performance of these agents has also been optimized, allowing for once-daily dosing of a subset of the newer fluoroquinolones.

In the first half of this chapter, an overview of the structural evolution of the quinolone agents is presented, with emphasis on the modifications that have provided advances in therapeutic utility. For ease of discussion, the examples largely consist of marketed quinolones and those in late-stage development, including a few whose development has been halted; the general structural themes, however, are representative of the much larger arena of investigational quinolone research. The reader is referred to numerous comprehensive reviews of SAR in the quinolone field [2-5].

General Structural Features of the Quinolones

As is evident from Figures 1 through 6, certain quinolone structural features remain constant throughout the class. Quinolone agents exhibit a bicyclic aromatic core; this can contain a carbon at the 8-position, yielding a true quinolone, or a nitrogen, which provides a ring system technically termed a naphthyridone (Figure 1). In common usage, however, both quinolone and naphthyridone structures are encompassed in the class descriptor "quinolone antibacterial agents." Antibacterial activity requires the presence of the pyridone ring on the right-hand side, as shown in a general way in Figure 1. The carboxylic

FIGURE 1 Quinolone and naphthyridone nuclei; general structural features required for antibacterial activity.

acid at the 3-position and the ketone at C-4 are required, as is the R!-substituted nitrogen at the 1-position.1 Substitution at C-2 is generally deleterious, although exceptions have been described in which the C-2 substituent forms a ring with R1 (see NM394 and prulifloxacin, Figures 4 and 8). In the left-hand ring, the fluorine at C-6 is found in essentially all the modern agents; it is because of this substituent that the class is often referred to as the fluoroquinolones (but see section on "Compounds Lacking the C-6 Fluorine"). A cyclic diamine R2 is most often present, attached through one of its nitrogens to the 7-position.2 Some variation is permitted at C-5 and the 8-position. Although the older quinolone agents were generally unsubstituted at C-5 (R3 = hydrogen), several more recent compounds bear small substituents such as amino or methyl at this site. At the 8-position, when X = carbon, a number of small substituents such as fluorine, chlorine, and methoxy have been found to provide improved potency.

In all the figures, structures represent racemic compounds unless they are labeled with stereochemical descriptors.

First-Generation Quinolones

The first quinolone antibacterial agent had its origins in a serendipitous discovery in the early 1960s. In the course of carrying out a synthesis of chloroquine, chemists at the Sterling-Winthrop laboratories in Rensselaer, New York, isolated compound 1 (Figure 2) as a byproduct, which was found to exhibit some antibacterial activity. Iterative chemical modification, through synthesis of similar compounds and assessment of their relative potency, led to the discovery of nalidixic acid (Figure 2), an agent with moderate activity against Gram-negative organisms, and the first of the quinolone antibacterials [6]. Nalidixic acid was introduced in the United States in 1963 as a therapeutant for urinary tract infections.

1It is a fascinating aspect of the quinolone field that, over time, almost all the dogma regarding structural requirements for activity has fallen, through the ingenuity of chemists in designing new modifications (see reviews cited in [2-5]). Thus, nearly all the strict requirements outlined in the text have exceptions in the research literature (see the section on "Future Directions"). In terms of marketed and late-stage clinical agents, these structural features have held constant. However, note T-3811 in the section on "Compounds Lacking the C-6 Fluorine."

2These diamines are generally based on 5- and 6-membered rings:

pyrrolidine piperazine piperidine pyrrolidine piperazine piperidine

FIGURE 2 Historical evolution of quinolones.

This new class of antibacterials sparked substantial worldwide interest in preparing and testing compounds of this type. Through the 1960s and 1970s, a number of related agents were developed (Figure 3). These first-generation quinolones reflect the early experimentation with the original nalidixic acid structure. Although all these agents retain a nitrogen atom at the 1-position, the naphthyridone structure of nalidixic acid was modified by returning to the quinolone nucleus (e.g., oxolinic acid) of the original lead compound 1. Insertion of additional nitrogen atoms into the quinolone and naphthyridone nuclei was effected at the 2-position (cinoxacin) and the 6-position (piromidic and pipemidic acids). Additional rings were fused at the 6- and 7-positions (oxolinic acid and cinoxacin) and across the 1- and 8-positions (flumequine). Addition of cyclic amines as substituents at the 7-position produced piromidic and pipemidic acids. The ethyl group on the nitrogen at the 1-position was left relatively constant; it was thought at that point that an N-1 substituent could not be larger than ethyl and retain good antibacterial potency [7].

These compounds generally displayed increased Gram-negative activity over nalidixic acid, but lacked useful activity against Gram-positive cocci (flumequine and oxolinic acid are the only first-generation agents with any substantial

Pipemidic Acid FIGURE 3 First-generation quinolones.

Gram-positive activity), Pseudomonas aeruginosa, and anaerobes. They were, however, generally well absorbed after oral administration and attained high concentrations in the urinary tract, making them useful therapeutically for treatment of urinary tract infections [8,9].

Second-Generation Quinolones

A major advance in the quinolone field came in 1980, when chemists at the Kyorin company reported the preparation of norfloxacin, in which the cyclic diamine piperazine found in pipemidic acid is combined with the 6-fluorine found in flumequine (Figures 2 and 4) [10]. Norfloxacin exhibits some Gram-positive activity in addition to improved Gram-negative action over the earlier agents, but in practice is confined to the historical quinolone indications of urinary tract infection and treatment of sexually transmitted disease and prostatitis, due to poor serum levels and tissue distribution. Norfloxacin was the first of the fluoroquinolones, so named because of the fluorine at the 6-position. Later studies revealed that introduction of this atom serves both to increase quinolone activity against the enzyme target DNA gyrase and to facilitate penetration into the bacterial cell [11]. The utility of the 6-fluorine in enhancing potency is so substantial that it has remained essentially inviolate in the quinolones investigated since 1980 (see, however, the section on "Compounds Lacking the C-6 Fluorine").

FIGURE 4 Second-generation quinolones.

Some of the modifications to the norfloxacin structure (Figure 4) seem relatively modest, yet the properties of the resulting analogues can be markedly altered, attesting to the potent influence of chemical structure on biological properties. For instance, addition of a methyl group to the distal nitrogen of the piperazine in norfloxacin yields pefloxacin, which exhibits a half-life more than twice that of norfloxacin [12]. Enoxacin, the naphthyridone analogue of norfloxacin, possesses roughly similar antibacterial activity but improved bioavailability over norfloxacin [13].

Introduction of fluorine atom(s) and addition of a methyl group onto the piperazine of norfloxacin produced fleroxacin and lomefloxacin (Figure 4). Although the antibacterial potency of these compounds is not generally improved over norfloxacin, they exhibit extended half-lives and significantly improved oral absorption [4]. Both of these compounds can be dosed once daily in the treatment of a variety of systemic infections.

Replacement of the N-1 ethyl group of norfloxacin by a cyclopropyl group yielded ciprofloxacin (Figures 2 and 4), which displays improved MIC values against Gram-positive and Gram-negative pathogens [14]. Ciprofloxacin, introduced in the United States in 1987 and the first of the quinolones to be useful in a variety of infections beyond the urinary tract and sexually transmitted diseases, is widely prescribed in the treatment of lower respiratory tract, skin, and joint infections.

Ofloxacin (Figure 4) has a nucleus that again borrows a feature from the first-generation quinolones: the tricyclic core is reminiscent of flumequine (Figure 2). Ofloxacin, marketed in the United States in 1991, was the second of the more broadly useful fluoroquinolone agents and has also been applied in a variety of systemic infections [15]. Rufloxacin (Figure 4) is derived from ofloxacin through replacement of the ring oxygen by a sulfur atom. Although this compound is generally less potent than norfloxacin [16], it is of note due to its unusual pharmacokinetics. The half-life of rufloxacin has been measured at >28 hr [2], significantly longer than any of the other quinolones. NM394, a later entry into the second generation, exhibits Gram-positive and Gram-negative activity similar to that of ciprofloxacin (see the section on "Activity against Gram-Negative Pathogens"). As mentioned above, this unusual structure is a departure from typical quinolones due to the C-2 substitution.

The N-1 ethyl group is present in all of these bicyclic compounds except NM394, in which the ethyl is now part of a four-membered ring, and ciprofloxacin; the cyclopropane of ciprofloxacin subsequently became the predominantly employed N-1 substituent, as can be seen by the later compounds shown in Figures 5 and 6, whereas the ethyl group has fallen almost completely out of use.

FIGURE 5 Third-generation quinolones.

Notes: development discontinued; ^ withdrawn from the market in October 1999; cwithdrawn from the market in 1992 [32].

FIGURE 5 Third-generation quinolones.

Notes: development discontinued; ^ withdrawn from the market in October 1999; cwithdrawn from the market in 1992 [32].

FIGURE 6 Fourth-generation quinolones.

Notes: ^development discontinued; ^development discontinued in December 1999; limited to serious infections in institutional settings as of June 1999.

FIGURE 6 Fourth-generation quinolones.

Notes: ^development discontinued; ^development discontinued in December 1999; limited to serious infections in institutional settings as of June 1999.

In the second-generation quinolones, it is also notable that the piperazine ring remains relatively undisturbed, except for alkylation on the distal nitrogen or, less frequently, on the ring carbons. As can be seen from the later quinolones (Figures 5 and 6), use of a cyclic amino group at C-7 is almost universal. The presence of a second amine, in addition to the nitrogen bonded to C-7 of the quinolone nucleus, is not required for in vitro activity, but has been found to be important for good activity in vivo [17].3

These second-generation compounds are characterized by good to excellent Gram-negative activity, with ciprofloxacin exhibiting the strongest Gram-nega-

3It is interesting to note that nadifloxacin, the sole marketed modern quinolone without a distal amine, is a topical agent [18]:

Nadifloxacin (OPC-7251)

Nadifloxacin (OPC-7251)

tive spectrum. These potency improvements are directly related to increasing potency against the enzyme target DNA gyrase. A linear correlation has been identified between the MIC against Escherichia coli for these agents and interaction with gyrase, as measured either by inhibition of supercoiling or cleavable complex formation [19]. The Gram-positive potency of these agents is also enhanced over that of the first-generation quinolone agents. However, these compounds are characterized by only moderate activity versus Staphylococcus aureus, a fact that may have contributed to the rapid rise in resistance to quinolones among methicillin-resistant S. aureus (MRSA) shortly after the introduction of ciprofloxacin into hospital usage [20]. Additional deficiencies in the spectrum of these agents lie in the areas of anaerobes, against which only marginal activity is observed, and the important respiratory Gram-positive pathogen Streptococcus pneumoniae. These agents also require multiple doses per day, with the exception of lomefloxacin, fleroxacin, and rufloxacin. While these three quinolones do offer once-daily dosing, their antibacterial potency is substantially less than that of ciprofloxacin. Fleroxacin and lomefloxacin also induce substantial photosensitivity [21]. All these deficiencies are addressed in the third generation of quinolone agents.

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