Fluoroquinolones: Synthesis and Application

Abstract

The data on 6-fluorо-1,4-dihydroquinolin-4-oxo-3-carboxylic acids and their structural analogues accumulated in the literature for the last 10–15 years are reviewed. Synthetic approaches to the quinolone system, as well as all kind of structural modifications by incorporating substituents into 1–8 positions or by means of annelation have been discussed. The “structure-activity” relationships for antibacterial fluoroquinolones, as well as the data on other types of biological activity for the family of bi- and polycyclic fluoroquinolones are presented. The formation of complexes of fluoroquinolones with metals and their applications have been considered. The bibliography – 377 references.

1 Introduction

Nearly three decades passed since the time when the first representatives of the fluoroquinolone family of antibacterials, such as norfloxacin, pefloxacin, ciprofloxacin and ofloxacin had appeared in the world pharmaceutical market (Scheme 1).

Scheme 1

Structure of some fluoroquinolone antibacterials

It is worth mentioning that the first drug in the series of quinolones, nalidixic acid (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-carboxylic acid), bearing no fluorine atoms, was launched into medicinal practice in 1963.

Structural modification of the quinolone skeleton by incorporating of fluorine atoms at C-6 and other positions of the benzene ring resulted in a remarkable improvement of antimicrobial properties and opened new prospects in clinical treatment of infections. Indeed, compounds of the fluoroquinolone family proved to exhibit a high level of antibacterial activity and a wide spectrum which surpass many antibiotics, including the third generation of cephalosporin’s and other chemotherapeutic antibacterials [1–13]. Due to enhanced penetration ability through cell membranes and their effects on bacteria reproduction by inhibiting bacterial DNA-gyrase, fluoroquinolones possess a high antibacterial activity (Fig. 1) [6].

Fig. 1

Inhibiting bacterial DNA-gyrase by fluoroquinolones (Reproduced with permission of publishing Folium [6])

It is extremely important that fluoroquinolones have a specific mechanism of action, different from antibiotics and other groups of antibacterials (cephalosporins, aminoglycosides, etc.), which allows one to apply fluoroquinolones for treatment of infectious diseases caused by strains resistant to many other classes of antibacterials drugs.

Depending on their behavior relative to bacteria enzymes of three types of fluoroquinolones can be distinguished:

• the first type of fluoroquinolones inhibiting mainly the topoisomerase IV: norfloxacin, enoxacin, fleroxacin, ciprofloxacin, lomefloxacin, trovafloxacin, grepafloxacin, ofloxacin and levofloxacin;

• the second type of fluoroquinolones which inhibit mainly the DNA-gyrase (nadifloxacin and sparfloxacin);

• the third type of fluoroquinolones which have a double effect: they inhibit both topoisomerase IV and DNA-gyrase: gatifloxacin, pazufloxacin, moxyfloxacin, and clinafloxacin.

An important feature of fluoroquinolones is their selective biological action: suppressing bacterial DNA-gyrase, they don’t influence the mammalian DNA cell processes. In fact, quinolones don’t kill bacteria by inhibiting critical cellular processes, but rather break action of two essential enzymes, DNA-gyrase and topoisomerase IV, and use them by causing a rupture of two-spiral DNA.

During the last two decades the whole series of antibacterial fluoroquinolones have found their application in clinical practice, thus demonstrating a beginning of a new era in chemotherapy of bacterial infections. The vast majority of fluoroquinolones, launched into medical practice, are based on the bicyclic structure of 6-fluoro-4-oxo-1,4-dihydroquinolin-3-carboxylic acid. Annelation of the benzene ring, and carbo- or heterocyclic fragments to the quinolone skeleton usually allow one to enhance antibacterial activity of fused fluoroquinolones and their therapeutical properties; in some cases derivatives of this class become capable of exhibiting other types of activity, including antiviral and antineoplastic ones. The most known representatives of tricyclic fluoroquinolones appear to be ofloxacin and levofloxacin. For many years fluoroquinolones have been intensively studied worldwide as evidenced by numerous review articles and monographs [1–13].

2 Synthesis and Antibacterial Activity of Fluoroquinolones

2.1 Bicyclic Fluoroquinolones

There are two basic approaches which are commonly used for the synthesis of quinolin-4-one-3-carboxylic acids [4, 14]. The first one is based on use of fluorinated anilines (1, A = CH, CF) or 2-aminopyridines (1, A = N) as starting materials and involves their condensation with ethoxymethylene derivative of malonate, cyanoacetate or acetoacetate to form enamines 2. The intramolecular cyclization of compounds 2 with polyphosphoric acid (PPA) (the Gould-Jacobs reaction) affords the corresponding fluoroquinolones (3, A = CH, CF) or naphthyridones (3, A = N) (Scheme 2).

Scheme 2

Synthesis of fluoroquinolones from fluorinated anilines

One of the key problems of the Gould-Jacobs reaction is a choice of high-boiling solvent. Diphenyl ether which has been applied for a long time is not appropriate due to environmental reasons. A good alternative of Ph₂O seems to be a summer diesel fuel, which is cheaper than individual C₁₂-C₁₈ hydrocarbons, and allows one to carry out the process at 230–245 °С providing a good purity of the key intermediates in the synthesis of fluoroquinolones.

The second approach suggests use of fluorine-containing benzoyl derivatives (4, A = CF, CH) or their nicotinoyl analogs (4, A = N) as building-blocks (Scheme 3). The key intermediates in this case are benzoyl- or pyridinoyl acrylates 6 [6]. Cyclization of enaminones 7 can be carried out by heating in DMF in the presence of potassium carbonate, or in ethyl acetate with NaH. Other basic conditions can also be applied, including organic amines or amidines, 1,4-diazabicyclo[2.2.2]-octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) [4, 15].

Scheme 3

Synthesis of fluoroquinolones from fluorinated benzoyl derivatives

The method can be improved by use of the dimethylamino analogue of intermediate 7, which can be derived from the reaction of ethyl 3-dimethyl aminoacrylate with the corresponding fluorine-containing benzoyl chlorides followed by the displacement of the dimethylamino group with a suitable amine.

A great deal of research studies aimed at improvement of synthetic procedures leading to fluoroquinolones, enhancing their yields and quality of products, and reducing a number of steps and cost of the synthesis have been performed [16–31]. Improved synthetic procedures have been applied to obtain 1-ethyl-6-fluoro-7-(4-methylpiperazinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid and 1-ethyl-6-fluoro-7-(piperazinyl-1)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid as well as their intermediates [18–21]. Further research studies on the synthesis of more active bicyclic fluoro-quinolones to expand a range of their biological activity, and to develop antibacterial drugs against resistant strains are in progress now.

2.1.1 Modification of the Position N(1)

The nitrogen atom N-1 and N-substituents are important features of the molecule of fluoroquinolones because of their considerable contribution into antibacterial activity. Replacement of the nitrogen atom with a carbon or oxygen in analogues of the oxolinic acid results in complete deactivation of these molecules. Modification of NH fluoroquinolones is usually based on N-alkylation reaction with the corresponding alkyl halide in the presence of a base. The first representatives of commercial fluoroquinolones bearing the ethyl group at N(1) are presented by norfloxacin, pefloxacin, and enoxacin; fleroxacin has N-fluoroethyl substituent, while amifloxacin contains the N-methylamino group. Research study on activity of the series of analogues of enoxacin, bearing C₁-C₅ aliphatic groups at N(1) have shown the preference of the N-ethyl group [32].

Modification of the N-ethyl group by means of incorporation of a fluorine atom (CH₂CH₂F, fleroxacin) appeared to be a reasonable approach [33]. Also conformationally restricted analogs of fleroxacin 9 and 10 have been synthesized (Scheme 4). The Z-isomers proved to be 2–32-fold more potent in vitro against gram-positive strains of bacteria then the corresponding E-isomers [34].

Scheme 4

Structure of fleroxacin and analogs

Replacement of N-ethyl group with NHCH₃ leads to a highly effective drug amifloxacin. Although it has not exhibited in vitro tests a considerable advantage in comparison with norfloxacin and pefloxacin, it shows a better pharmacokinetic profile, being equally active in both oral and parenteral administration.

It has been revealed that a high antibacterial activity of fluoroquinolones is associated with the presence of a small lipophilic group, such as, for instance, N-cyclopropyl substituent in position 1. Indeed, a number of commercially important fluoroquinolones bear the cyclopropyl fragment at N(1): ciprofloxacin, enrofloxacin, grepafloxacin, clinafloxacin, gatifloxacin, moxifloxacin (Scheme 5) [7].

Scheme 5

Structure of amifloxacin and 1-cyclopropyl-fluoroquinolones

Incorporation of methyl or phenyl substituents in the cyclopropane ring, as well as the replacement of the cyclopropyl moiety with cyclobutyl or cyclopentyl ones diminishes the activity of these derivatives (Table 1) [7].

Table 1 Activity of N(1)-substituted fluoroquinolones (MIC, μg/ml)

Further modification of the cyclopropyl fragment (for example, 2-fluorocyclopropyl derivatives 11) gives rise to optically active isomers, which differ considerably in their activities, as illustrated by the fact that cis-analogs are more active against gram-positive strains of bacteria, than the corresponding trans-isomers, for example, cis-isomer of fluoroquinolone 11 (R₇ = 4-methyl-piperazin-1-yl) shows MIC 0,1 μg/ml against St. aur., while trans-isomer has only 1,56 μg/ml. New synthetic approaches enabling one to introduce at N-1 of fluoroquinolones a fluorine-containing cyclopropyl fragment with a certain stereo-configuration have been developed [35, 36].

Incorporation of benzyl or t-butyl groups at N-1 enhances antibacterial activity of fluoroquinolones [37, 38]. Monofluoro-t-butyl derivatives proved to possess a higher antibacterial activity than their non-fluorinated analogs. An opportunity to use 1-trifluoromethyl-1,2-ethylenediamines for modification of position 1 of fluoroquinolones (compounds 12) (Scheme 6) [39] has been shown.

Scheme 6

Structure of fluoroquinolones 11 and 12

Derivatives of bicyclic pefloxacin 13 and 14 represent an interesting type of hybrid molecules, in which N-butylfluoroquinolone fragments are linked with the pyrimidine and purine heterocyclic bases (Scheme 7) [40].

Scheme 7

Structure of fluoroquinolones 13 and 14

Fluoroquinolones 15 bearing the (hydroxyethoxy)methyl fragment, which is present in acyclovir, the known antiviral agent, can be regarded as acyclic analogs of nucleosides (Scheme 8) [41]. Also 5′-thioalkyl acyclic nucleosides of fluoroquinolones have been obtained by the reaction of mesylate 15 with methanethiolate- or thiophenolate anions [42].

Scheme 8

Structure of fluoroquinolones 15 and 16

A series of new quinolones 16 bearing the fragments of natural amino acids have been synthesized. According to the data of preliminary biological studies these fluoroquinolones exhibit antibacterial activity against Bacillus subtilis and Staphylococus aureus [43].

Synthetic routes to new fluoroquinolones, containing in position 1 aryl substituent have also been described [44–46]. As a rule, a fluorophenyl substituent with one or two fluorine atoms has a favorable effect, increasing an activity of fluoroquinolones towards anaerobic bacteria. It has been found that 1-(5-amino-2,4-difluorophenyl)-8-R-substituted quinolones 17 possess a rather high antibacterial activity relative to Gram-positive and Gram-negative microorganisms (Scheme 9) [47]. 7-(Methylpiperazinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-qui-nolincarboxylic acids (difloxacin) has been established to be one of the most active fluoroquinolones in experiments in vitro against Chlamydia trachomatis and other intracellular parasites; also it demonstrates excellent pharmacokinetic properties. Also, the antibacterial drug linezolid 18 bearing at N-1 2-fluoro-(4-oxazolidon-1-yl)phenyl fragment has been developed [48] (Scheme 9). N-(5-Amino-2,4-difluorophenyl)-7-aminoazetidinyl-8-chloro-substituted fluoroquinolone has been found to possess a high antibacterial activity relative to Gram-positive and Gram-negative microorganisms; its activity against Strentococcus pneumoniae proved to be 30-fold higher than that of trovafloxacin.

Scheme 9

Structure of fluoroquinolones 17 and 18

A number of researches were dedicated to incorporating of heterocyclic fragments in position 1 of fluoroquinolones in expectation of enhanced activity [49]. Indeed, 1-(6-amino-3,5-difluoropyridin-2-yl) substituted quinolone 19 (Scheme 10) proved to be rather promising for treatment of serious respiratory diseases and infections of the urinary tract. This fluoroquinolone has a wide range of antibacterial activity, including quinolone-sensitive and resistant staphylococcus and streptococcus, vancomicin-sensitive and resistant enterococcus, anaerobic bacteria and other infections [50], 20 was shown to be more active than ciprofloxacin [51] (Scheme 10).

Scheme 10

Structure of fluoroquinolones 19 and 20

1-Trifluoromethylated fluoroquinolone shows antibacterial activity at the level of norfloxacin [52]. 1-Hydroxy-2-phenyl- and 1-hydroxy-2-methyl substituted quinolones have been obtained, however they have not shown a remarkable level of antibacterial activity [53, 54].

Analysis of the data of biological trials for N-substituted fluoroquinolones available in literature enables to conclude that compounds bearing in position 1 cyclopropyl, fluorophenyl or t-butyl fragments exhibit a higher level of antibacterial activity than their N-unsubstituted analogues.

2.1.2 Modification of the Position C(2)

Modifications of the C(2)-position are limited due to synthetic difficulties associated with direct introduction substituents at C-2. However, the synthesis of 2-phenylsubstituted fluoroquinolones has been developed [55], and 6-fluoro-quinolon-2-carboxylic acids have been obtained by cyclization of the corresponding 2-aminosubstituted 3-pentafluorobenzoyl acrylic acids [56]. 2-Thio substituted quinolones are widely used for the synthesis [a]- or [b]-annelated fluoroquinolones, such as thiazolo- and azethydinoquinolones [57–59]. Synthesis of 1-cyclopropyl-2-alkylthio-8-methoxyfluoroquinolones was described; however elucidation of their antibacterial activity revealed no regularities associated with incorporation of 2-alkylthio substituents [60]. All known 2-aza analogues of quinolones and naphthyridines, derivatives of cinnoline, have not exhibited any remarkable antibacterial activity.

2.1.3 Modification of the 3-Carboxyl Group

Modifications of the 3-carboxyl group appear to be worth only in those cases where these derivatives are considered as precursors of the corresponding carboxylic acids [61], however precursors not always exhibit activity in vivo. Replacement of the 3-carboxyl group with acyl, ethoxycarbonyl, methoxycarbonyl and other acidic fragments (hydroxamic, acetic, phosphonic, sulphinic or sulpho) results in complete loss or diminishes dramatically antibacterial activity of these compounds.

Functional properties of the carboxyl group have been used to modify it with osteofilic bisphosphonate fragments, as exemplified by structural modifications of moxi-, gati- and ciprofloxacin are developed [62]. Derivatives of these fluoroquinolones 21, containing bisphosphonate ester, thioester or amide groups have been obtained (Scheme 11). Their abilities to contact bones and to recycle thus active medicinal component have been studied. It has been shown that bisphosphonate derivatives of fluoroquinolones are osteotropic predecessors for prevention of osteomielit.

Scheme 11

Structure of fluoroquinolones 21

Amides, hydrazides, and thiourea derivatives are important derivatives of fluoroquinolones [63–65]. It is worth noting that 7-chloroquinolones bearing the amide moiety at C-3 are rather active against B. subtilis and S. aureus. Also phenylthiourea derivatives proved to be more active against B. subtilis than the parent ciprofloxacin [64]. Synthesis of glycosylhydrazides and aminoacids on the basis of the corresponding hydrazido- and azido derivatives of 6-fluoroquinolin-4-one-3-carboxylic acids has been described [66].

Esters and hydrazides of 6-fluoroquinoline-4-oxo-3-carboxylic acids have been used for modification of the position 3 through the formation of heterocyclic fragments, such as oxadiazole, triazole, thiadiazole, benzofuropyrazoline, thiazolidine and others [67, 68]. Synthesis of fluoroquinolones containing in position 3 quinoxalinone, benzoxazinone and benzothiazinone fragments has recently been described [69, 70]. This synthesis was realized through interaction of fluoroquinolones bearing EtOC(O)C(O) residue with aromatic 1,2-binucleophiles. 3-Formyl- and acetyl derivatives of fluoroquinolones and also alcohols and amines have been obtained through transformation of amides [71].

It has been established that after oral administration of 3-formyl analogue of norfloxacin in mice the formyl group is metabolized rather fast into the carboxyl one, thus converting 3-formyl derivatives into norfloxacin. Due to a good solubility, a much higher level (at least two times) of the formyl derivative in blood serum can be reached, than on administration of norfloxacin, which at physiological рН values exists in the form of poor soluble zwitter-ionic form.

During the last two decades a lot of attention has been paid to development of “double mechanism” antibiotics. One of plausible approaches to such compounds is esterification of fluoroquinolone carboxylic acids with derivatives of cephalosporin and penicillin. Such combination allows one to expand a spectrum of antibacterial activity of beta-lactams conjugated with quinolones due to complementary mechanisms of their actions [7, 72].

Displacement of the carboxyl group in position 3 with hydrogen atom and the decarboxylation of fluoroquinolones have been discussed in the literature [73–76]. Since no decarboxylated fluoroquinolones have exhibited antibacterial activity, many authors have come to conclusion on the extremely importance of the 3-carboxy group.

2.1.4 Modification of the 4-Oxo Group

The oxo group can be modified through the formation of oximes, hydrazones, and semicarbazones, as exemplified by transformations of norfloxacin and other fluoroquinolones [73]. Specific methods are needed to convert fluoroquinolones into their 4-alkoxy analogues, due to a preferable N-alkylation of fluoroquinolones at position 1. Another modification is the synthesis of 4Н-1,4-benzothiazin-1-oxides and 1,1-dioxides [77] with various substituents in the benzene ring. However, these compounds proved to exhibit neither antibacterial activity, nor they inhibit DNA-gyrase. These results show that SO and SO₂ groups in quinolones cannot be regarded as bioisosters of the carbonyl group.

It has to be concluded that the oxo group at C(4) is necessary for linkage of quinolones with DNA-gyrase, and elimination or replacement of the oxo fragment with other moieties lead to inactive compounds.

2.1.5 Modification of the Position С(5)

The most promising results have been received in those cases when the amino group was introduced at position 5 of fluoroquinolones. The detailed analysis of the “structure–activity” relationship for 5-substituted 1-cyclopropyl-6-fluoro-quinolones has shown that the positive effects of NH₂ and CH₃ groups are approximately identical, and these fluoroquinolones possess a wide range and high level of antibacterial activity [7]. Indeed, 7-(7-aminomethyl-5-azaspiro[2.4]heptan-5-yl)quinolone 22 proved to be 12 times more active against S. aureus HPC527 than ciprofloxacin [78, 79]. The methoxy derivative 23, and also its 8-methyl analogues show a high antibacterial activity towards a great deal of microorganisms [80] (Scheme 12). 5-Also acylaminoquinolones have been synthesized [81].

Scheme 12

Structure of 5-aminofluoroquinolones 22, 23

In order to obtain multi-binding therapeutic agents that modulate enzymatic processes, two fluoroquinolone ligands were linked at positions 5 through 1,3-di-aminopropane bridge (compound 24) [82]. Fluoroquinolones bearing the hydrazino group in position 5 appear to be effective antimicrobials towards a number of pathogenic microorganisms; also they possess a good solubility in water relative to other fluoroquinolones [83]. 5-Methoxy- and 5-hydroxy-6-fluoro-1,8-naphthyridin-4-oxo-3-carboxylic acids (25a,b) are more active against S. pneumoniae 7257 than levofloxacin [84] (Scheme 13).

Scheme 13

Structure of fluoroquinolones 24, 25

Incorporation of such substituents as Cl, Br, SH, SCH₃, CHO into position 5 of 1-cyclopropyl-6,8-difluoro-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-3-quinolincarboxylic acids didn’t result in substantial increase of their activity. Some substituents at C(5) have a negative effect on antibacterial activity of fluoroquinolones which can possibly be explained by steric hindrance to interaction of the 4-oxo-3-carboxy-fragment of fluoroquinolone molecules with metal ions of the bacterial DNA-gyrase. However, a fluorine atom at C-5 with nearly the same space volume as a hydrogen one also diminishes the activity of fluoroquinolones, and it can’t be connected with its steric effect.

2.1.6 Modification of the Position С(6)

Replacement of a fluorine atom in position 6 with other substituents didn’t enhance their activity, at the same time it was shown that in order to obtain highly active antibacterial compounds the presence of fluorine atom at C(6) is not obligatory, it is more important to have in the quinolone skeleton the N(1)-cyclopropyl and C(7)-3-aminopyrrolidinyl pharmacophoric groups (Table 2) [85–88].

Table 2 Antibacterial activity of mono- and difluoroquinolones (MIC, μg/ml)

Studies of antibacterial activity of 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones and their C(6)-defluoro analogs showed that all of them are in 4–520 times more active against gram-positive bacteria, than trova-, moxi-, gati- or ciprofloxacin [89]. These quinolones have shown the indices of activity against Gram-negative bacteria E. coli and K. pneumoniae which are comparable with those of trova- and ciprofloxacin.

Incorporation of the nitrogen atom (derivatives of 1,6-naphthiridines) proved to diminish considerably the activity of quinolones.

2.1.7 Modification of the Position С(7)

A great deal on the chemistry of 6-fluoroquinolones concerns modification of the position 7. It is due to the fact that a halogen atom at C(7) undergoes easily nucleophilic displacement with N-, S-, O- and C-nucleophiles, thus allowing one to vary the structure of quinolones. Nearly all commercially important fluoroquinolones contain at C-7 the fragments of cycloalkylimines [90–94].

Quinolones bearing in position 7 small or linear substituents, such as H, OH, OEt, COOH, Cl, Me, NH₂, NHR, NH-c-C₃H₅, NHNH₂, SCH₂CH₂NH₂ etc., have a relatively low activity against gram-positive microorganisms and are practically inactive towards the negative bacteria. Also 7-aza analogues of 6-fluoroquinolon-3-carboxylic acids, derivatives of 1,7-naphthyridines, didn’t show any remarkable antibacterial activity.

A lot of studies have been directed to the synthesis of fluoroquinolones, bearing a variety of piperazinyl substituents, since this part of quinolone molecule is of significant importance. Indeed, some representatives of 6-fluoroquinolones bearing at C(7) piperazine (norfloxacin, ciprofloxacin), 4-methylpiperazine (pefloxacin), 3-methylpiperazin (lomefloxacin, temafloxacin) proved to possess a much broader range of antibacterial activity, than those without the piperazine moiety, such as nalidixic and oxolinic acids.

In order to introduce the piperazine residue into position 7 of fluoroquinolones the reaction of 7-chloroquinolone with N-alkoxycarbonylpiperazine in high-boiling dipolar aprotic solvent followed by hydrolysis of alkoxycarbonyl group has been exploited. In some cases the borondiacetate complexes of fluoroquinolones have also been used for introduction of the piperazine fragment.

The difference in activity for R- and S-enantiomers of 7-(3-methylpiperazin-1-yl)quinolones, obtained from the corresponding (R)- and (S)-t-butyl-2-methylpiperazin-1-carboxylates, proved to be in the range from 2 to 64 folds in 52 % of cases [95]. In order to improve transport through biological membranes the piperazine moiety in norfloxacin was modified considerably and compound 26 was obtained [96]. To clarify the mechanism of antibacterial action of fluoroquinolones at the cellular level, two regioisomeric citrate-functionalized derivatives of ciprofloxacin 27a,b [97] (Scheme 14) have been obtained and studied.

Scheme 14

Structure of fluoroquinolones 26, 27

Introduction of spiropiperazine or piperazinedione groups in position 7 of 1-cyclopropyl substituted fluoroquinolones has been shown to enhance their antimicrobial activity (compounds 28a,b) (Scheme 15) [98, 99].

Scheme 15

Structure of fluoroquinolones 28

Also the piperazine fragment of fluoroquinolones was modified by introduction of a number of heterocyclic fragments, such as 2,6-diaminopyrimidinyl, 4,6-diamino-1,3,5-triazinyl, 2-aminothiazinyl, 1,3,4-thiadiazolyl, 2-furyl and other groups, thus allowing one to obtain more active antibacterial drugs [100–103].

Hybrid derivatives of fluoroquinolones bearing fragments of penicillin and cephalosporin antibiotics or uracils, for example compounds 29–31, proved to possess a wide spectrum and high level of antibacterial activity, including their potency against resistant to β-lactams strains [74, 104–107] (Scheme 16). High antibacterial activity has also been shown by 7-(N-aryl-2,2,2-trifluoroacetimidoyl)piperazinyl derivatives of fluoroquinolones [108].

Scheme 16

Structure of fluoroquinolones 29–31

Influence of the second heteroatom in the piperazine ring is not so unequivocal. For instance, the replacement N(4) in the piperazine moiety of amifloxacin with O, S or CH₂ fragments has been shown to diminish activity of these compounds in vitro and in vivo, however when the piperazine residue in norfloxacin was replaced with thiomorpholine a much more potent compound against Gram-positive bacteria has been obtained. 7-(3-Aminomorpholin-1-yl) and 7-[3-(or 4)-aminomethylpiperidin-1-yl]-derivatives proved also to possess a high activity against St. aur. (Table 3). 7-Azetidinyl substituted fluoroquinolones, in particular trans-3-amino-2-methyl-1-azetidinyl derivatives proved to be highly active antibacterial compounds [84, 109, 110].

Table 3 Antibacterial activity of 7-substituted fluoroquinolones (MIC, μg/ml)

A large group of highly active fluoroquinolones contains the pyrrolidine fragment in position 7, and, therefore, a considerable attention has been paid to the synthesis of 6-fluoro-7-pyrrololidinoquinolones with 3-amino-, 3-aminomethyl- or 3-(2-cyanomethylamino) substituents in the pyrrolidine ring [111–114]. As a rule, the compounds of this series possess a much higher activity towards Gram-positive microorganisms than the corresponding piperazine derivatives.

Fluoroquinolones 32a, containing alkyloximino substituent at C-4 and the aminomethyl fragment at position 3 of the pyrrolidine ring, exhibit a high antibacterial activity towards Gram-positive and Gram-negative microorganisms, including a methicillin-resistant strain of S. aureus (MRSA) [115–118]. Compounds 32b having an optically active center in the pyrrolidine ring and the methyloximino group proved to possess not only high antibacterial activity, but also a good pharmacokinetic profile [119, 120]. Also, the series of fluoroquinolones, containing spiropyrrolidine substituents at C-7, for example, compound 33a, have been obtained (Scheme 17) [121, 122].

Scheme 17

Structure of fluoroquinolones 32, 33a

Effects of the chiral fragments, such as 1-(cis-2-fluorocyclopropyl) and 7-(7-amino-5-azaspiro[2.4]heptyl) substituents (compounds 32b, 33a) on antibacterial properties of the series of fluoroquinolones have been studied (Scheme 18) [123]. It has been shown that derivatives of 1-[(1R,2S)-2-fluorocyclopropyl]- and 7-[(7S)-amino-5-azaspiro[2.4]heptyl]-fluoroquinolones are more active towards a number of Gram-positive and Gram-negative bacteria, than other stereoisomers. The presence of spiropyrrolidine residue at C(7) of fluoroquinolones enhances their lipophilic properties, thus promoting a better assimilation on oral administration [98].

Scheme 18

Structure of fluoroquinolones 33b, 34

Compounds 33b, 34 with the amino group attached to the spiropyrrolidine or cyclopropyl-substituted pyrrolidine fragment proved to exhibit broad spectrum of antibacterial activity (Scheme 18) [124–129]. Aminomethyl substituted pyrrolidines and their heterocyclic derivatives were incorporated into position 7 of fluoroquinolone [130–132]. Optically active derivatives of 7-(3-hydroxypyrrolidin-1-yl)-6-fluoroquinolones have been shown to be promising antibacterials [133–135].

One more residue which is frequently present in position 7 of active fluoroquinolones is piperidine [136–139]. Indeed, 1-cyclopropyl-6-fluoro-quinolones, containing (3S)-amino-(4R)-piperidinyl fragment in position 7, show a high activity towards resistant strains of Staphylococus aureus and Streptococus pneumoniae [140]. A number of substituents, such as 4-amino, 4-hydroxy, 3-aminomethyl, 4-aminomethyl and 3-methylamino were incorporated in the piperidinyl fragment [141, 142]. Novel 6-fluoroquinolones and naphthyridines with 4 (3)-alkoxyimino-3-aminomethyl-3-H(methyl)piperidinyl substituents, for instance 35, have been obtained (Scheme 19) [143–145]. They shown a high activity against all gram-positive organisms, including those resistant to fluoroquinolones. One of compounds of this series proved to be in 16–128, 2–32 and 4–8 times more active against fluoroquinolone-resistant MSSA, MRSA and MRSE than gemi-, cipro- and levofloxacin, respectively. Introduction of 4-(1Н-1,2,3-triazol-1-yl)piperidinyl residue in the structure of fluoroquinolone resulted in a good activity against S. aureus and S. epidermidis [146].

Scheme 19

Structure of fluoroquinolones 35–38

A very promising modification of fluoroquinolones is introduction of bridged cyclic amines in position 7 [147–153]. A series new fluoroquinolones 36 was synthesized (Scheme 19), and one of compounds showed high activity against quinolone-sensitive and multi-resistant bacteria, especially towards Streptococcus pneumonia [154].

Trovafloxacin 37, the very active compound with a wide spectrum of action, contains 7-(1α, 5α, 6α)-3-azabicyclo[3.1.0]hexyl substituent (Scheme 19) [155, 156]. 6-Fluoro-1-[(1R, 2S)-2-fluorocyclopropan-1-yl]-4-oxoquinolin-3-carboxylic acids, containing in position 7 2-amino-8-azabicyclo[4.3.0]nonan-8-yl fragment have been shown to inhibit bacterial DNA topoisomerase IV very effectively [157]. A great deal of research are dedicated to the synthesis and biological tests of 7-di- and triazabicyclononyl substituted 6,8-difluoroquinolones, for instance 38 (Scheme 19) [158–163].

An effective way for introduction of a variety of heterocyclic fragments in the position 7 of the fluoroquinolone skeleton is the methodology of 1,3-dipolar cycloaddition reactions [164–167]. Indeed, the reaction of 7-azido derivative of 6-fluoroquinolone 39 with enamines of cyclic ketones and norbornene proceeds rather smoothly with the formation of the corresponding exo-1,2,3-triazolines 40 which undergo the cationic rearrangements into amidines 41 or aminonorbornane 42 [164, 165]. 7-Azido derivatives 39 are capable of reacting with heterocyclic amines to form new 7- fluoroquinolones (Scheme 20) [168].

Scheme 20

1,3-Dipolar cycloaddition reactions of 7-azido derivative 39

Scheme 21

The cycloaddition reactions of azomethine 43

The cycloaddition reaction of azomethine 43 with alkenes proceeds in regio- and stereoselective manner and represents a convenient way to obtain a variety of stereoisomeric 7-isoxazolidinyl quinolones 44–48 [166, 167] (Scheme 21).

Scheme 22

Synthesis of fluoroquinolone 49

Synthesis of new hydroxybisphosphonate derivatives of ciprofloxacin 49 has been performed by using Cu-catalyzed 1,3-dipolar cycloaddition reaction between the corresponding azide and N-alkynyl substituted quinolone [169] (Scheme 22). Derivatives of gati- and moxifloxacin have been obtained similarly. All of these modified compounds maintained antibacterial activity of the starting quinolones and, in addition to that, exhibit osteotropic properties.

A number of 6-fluoroquinoline- and 6-fluoronaphthyridine-3-carboxylic acids, containing at C(7) rather complicated fragment of multilinе (compounds 50) have been synthesized (Scheme 23) [170]. Quinolones 50 exhibit a high activity against resistant bacteria, in particular, methicillin- and quinolone-resistant Staphylococcus, Streptococcus pneumoniae, etc.

Scheme 23

Structure of fluoroquinolones 50, 51

Synthesis on the basis of organoelement compounds play an important role for modification of position 7 in fluoroquinolones [171]. As mentioned above, fluoroquinolones, containing hetaryl residues in position 7 are promising for medicinal chemistry [172]. In particular, a number of highly active fluoroquinolones have been obtained on the basis of 7-nitromethyl derivatives [173, 174]. The 7-(1,2,3,4-tetrahydropirrolo[1,2-a]pyrazin-7-yl) fragment has been incorporated in the structure of quinoline and naphthiridine carboxylic acids 51 through the carbon-carbon bond formation by reacting 7-halogeno or tosyl-substituted quinolones with the corresponding borates (Scheme 23) [175]. It should be noted that several compounds of this series have exhibited a high activity against ciprofloxacin-resistant bacteria of Streptococcus pneumoniae.

Thus, varying substituents in position 7 provides a good platform for development of novel antibacterial drugs. New opportunities for modification of position 7 are associated with design of hybrid molecules, as illustrated, for instance, by the development of the double action drugs containing both a fluoroquinolone and β-lactam antibiotic fragments.

2.1.8 Modification of Position С(8)

The nature of substituents in position 8 of fluoroquinolones also makes a certain impact on antibacterial activity. The key role of the 8-methoxy substituent is demonstrated by the fact that this fragment is a part of such effective drugs, as moxifloxacin and gatifloxacin [176–180]. Indeed, fluoroquinolone 52 shows a high activity against H. influenza and M. catarrhalis [181], while compound 53 is 4 times more active against S. pneumoniae than levofloxacin [182, 183]. 8-Methoxy-6-fluoroquinolone 54 has smaller side effects on the cardio-vascular system, than gatifloxacin (Scheme 24) [184].

Scheme 24

Structure of fluoroquinolones 52–54

Fluoroquinolones, containing 8-methyl substituent usually demonstrate a high antibacterial activity, e.g. olamufloxacin is of great importance for treatment of urological diseases [185–188]. Also the cyano group in position 8 proved to be an appropriate substituent, as illustrated by the synthesis of 8-cyanoquinolones 55 and 56 [189] (Scheme 25). Indeed, compound 55 has been shown to possess a high antibacterial activity towards Gram-positive and Gram-negative bacteria [193], while 8-cyanoquinolone 56, containing the diazobicyclononane residue in position 7 is more active antibacterial compound than enrofloxacin (Scheme 25) [190]. Substituents NO₂, NH₂, SCH₃, CF₃ in position 8 have usually a negative impact on both in vitro and in vivo activities, especially towards Gram-negative microorganisms.

Scheme 25

Structure of olamufloxacin and fluoroquinolones 55, 56

In order to obtain “structure-biological activity” relationships mathematic methods have been used [191–193]. Quantitative correlations between molecular structure and pharmacokinetic and pharmacodynamic characteristics of fluoroquinolones in combination with informative hemometric approach have been used to forecast anti-pneumococcus activity [194]. Elucidation of the structure – activity relationships in the series of fluoroquinolones is the subject of numerous publications [195–197]. Dependence of antibacterial activity on the nature of substituents has been established for several series of bicyclic fluoroquinolones [11, 198–200].

2.2 Polycyclic Fluoroquinolones

Modification of fluoroquinolones by annelation of carbo- or heterocyclic rings leads to fused polycyclic systems (Scheme 26).

Scheme 26

Possible locations of additional rings in polycyclic fluoroquinolones

2.2.1 [a]-Annelated Fluoroquinolones

There are two principal approaches to the synthesis of [a]-annelated fluoro-quinolones. The first one suggests that an [a]-annelated ring is already involved in the structure of intermediates, such as aminoacrylates A or malonates B, followed by their cyclization into the corresponding fluoroquinolones. The second approach is based on use of 1- or 2-substituted quinolones C or D, which undergo intramolecular [a]-fusion (Scheme 27) [10].

Scheme 27

Approaches to the synthesis of [a]-annelated fluoroquinolones

The first approach has been used to obtain [a]-annelated fluoroquinolones 57 and 58 from the correspondingly substituted ethyl acetates and 2-chlorobenzazoles or iminoesters (Scheme 28). 7-(1-Piperazinyl)- and 7-(4-methyl-1-piperazinyl)-benzothiazolo-[3,2-a]quinolones 57 have been established to exhibit rather good activity against a number of bacteria [201].

Scheme 28

Synthesis of azolo[a]quinolones

Synthetic routes to [a]-fused quinolones of general formula 59 from the corresponding polyfluorobenzoyl chlorides and α-azahetaryl acetonitriles have been developed [202]. Heterocyclization of quinoxalones, containing polyfluoroaroyl fragment in position 3 in DMSO in the presence of triethylamine affords 60 (Scheme 29) [203].

Scheme 29

Structure of fluoroquinolones 59, 60

The [a]-annelation in which the starting material is N-methylaminoquinolone has been described [204, 205]. Use of the 1,4-addition to the activated multiple bonds followed by the Michael intramolecular reaction leads to tetrahydropyrazolo[1,5-a]quinolones 61, which are oxidized into the corresponding pyrazolo[1,5-a]quinolones. Hexahydropyrrolo[1,2-a]quinolones 62 can be regarded as [3 + 2] adducts derived from the reactions of N-(ethoxycarbonyl)methyl substituted ethyl esters of di-, three- and tetrafluoro-4-oxo-1,4-dihydroquinolin-3-carboxylic acids with methylmetacrylate (Scheme 30) [206].

Scheme 30

Structure of fluoroquinolones 61–64

Derivative of [1, 2, 4]triazino[1,6-a]quinoline 63 has been obtained from methyl 6-fluoro-4-oxo-1,4-dihydro-2-quinolincarboxylate through the N-amination followed by condensation of the corresponding aroyl isocyanate and cyclization of the obtained α-semicarbazidocarboxylate [207]. 8-Fluoro-4-hydroxy-1Н-[1,2,4]-triazino[4,5-a]-quinolin-1,6(2Н)-dione 64 has been obtained by condensation of 6-fluoro-4-oxo-1,4-dihydro-2-quinolinecarbohydrazide by action of phosgene [208]. 8-Fluoro-1,2-dihydro[1,4]oxazino[4,3-a]quinolin-4,6-dione was derived from intramolecular cyclization of 2-chloroethyl 6-fluoro-4-oxo-1,4-dihydro-2-quinolincarboxylate [209]. New tetracyclic system containing fluoroquinolone fragment 66 was obtained by intramolecular condensation of ethyl 3-acetyl-5-oxopyrazolo[1,5-a]quinolin-4-carboxylate 65 on heating [210] (Scheme 31).

Scheme 31

Synthesis of tetracyclic fluoroquinolone 66

2-Mercapto-6-fluoroquinolin-3-carboxylic acids are considered as important intermediates in schemes leading to [a]-annelated fluoroquinolones, as shown by the synthesis of a number of thiazeto[a]quinolones 67 possessing a high level of antibacterial activity (Table 4) [211–213]. For instance, modification of position 7 of thiazeto[3,2-a]quinolones results in the formation of highly effective tricyclic antibacterials, such as prulifloxacin 68, which is metabolized in organisms into ulifloxacin 69 (Scheme 32) [214–217]. It is worth noting that decarboxylation of ulifloxacin drops down the antibacterial activity in 60–12,000 times. A similar phenomenon has been observed in case of cipro- and moxifloxacin [60], thus showing an extremely important role of the carboxyl group. The synthesis of thiazolo[3,2-a]-, [1,3]benzothiazino[3,2-a]- and [1,3]benzothiazino[1,2-a]quinolin-6-carboxylic acids has also been reported [218, 219].

Table 4 Activity of 67 (R = Me, R² = R⁵ = H, R³ = F), MIC, μg/ml

Scheme 32

Structure of thiazeto[a]quinolones 67–69

It should be noted that [a]-annelation of additional rings through the reactions of1- or 2-substituted fluoroquinolones has certain restrictions, while cyclocondensation of fluorinated benzoyl chlorides with C,N-bifunctional nucleophiles appears to be a more common method for the synthesis of a broad range of [a]-annelated fluoroquinolones. Incorporation of original bicyclic amines at position 7, as well as the synthesis of new derivatives through reactions of the carboxyl group are the main directions for modification of [a]-annelated fluoroquinolones.

2.2.2 [b]-Annelated Fluoroquinolones

The thesis concerning necessity of the carboxyl group in position 3 of fluoro-quinolones to provide their antibacterial properties is not in agreement with the data on activity of [b]-annelated isothiazolo-, pyrido-, pyrimido- and pyrazino-quinolones which stimulated research studies of this group of compounds [7]. Indeed, a whole number of oxoisothiazolo[5,4-b]quinolones possessing a high antibacterial activity (Table 5), for instance compound 70a and its analogues, have been obtained [220–224]. Also 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]-quinolin-3,4-dione has shown a high activity in vitro against methicillin-sensitive strains of Staphylococcus aureus (MRSA), high level of inhibiting of DNA-gyrase and topoisomerase IV of S. aureus, in combination with a neglect able effect on human topoisomerase II and low cytotoxicity [225, 226]. A series of 7-(3′-substituted) pyrrolidinyl-8-methoxyisothiazolo[b]quinolones 71 has been obtained and their antibacterial activity towards methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, including stereochemical aspects and influence of substituents, has been elucidated [226].

Table 5 Antibacterial activity of [b]-annelated fluoroquinolones (MIC, μg/ml)

The synthesis of 1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinoline-9-one 72, inhibitor of protein kinase C, has been performed by means of cyclization of 4-[(4-fluorophenyl)amino]-1-methyl-1Н-pyrazole-5-carboxylic acid (Scheme 33) [227]. The main trends in development of research studies in the field of [b]-annelated fluoroquinolones are dealt with use of these compounds for the synthesis of novel [i,j]-annelated systems, a varying of substituents at C-7, and also with obtaining of new 2-substituted fluoroquinolones.

Scheme 33

Structure of [b]-annelated quinolones 70a-72

2.2.3 [с]- and [d,e]-Annelated Fluoroquinolones

The targeted synthesis of these types of fused fluoroquinolones has never been carried out, since the oxo-group in position 4 which is responsible for linkage of fluoroquinolones with DNA gyrase has to be eliminated [7].

2.2.4 [f]- and [g]-Annelated Fluoroquinolones

Both [f], and [g]-annelation results in loss of fluorine atom in position 6 the presence of which has long been associated with a high level of antibacterial activity of fluoroquinolones. However, a number of highly active compounds have been revealed in the series of oxazolo-, thiazolo- and imidazo[4,5-f] fused fluoroquinolones. For instance, derivative 73 (R³ = R⁴ = F) has shown a good activity against both Gram-positive, and Gram-negative bacteria [228]. According to in vitro biological tests 5-methoxyimidazo[4,5-f]quinolones 74 exceeds in activity the corresponding analogs of ofloxacin [229]. Furonaphthyridine 75 has found application as the basis to obtain antibacterials (Scheme 34) [230].

Scheme 34

Structure of [f]-and [g]-annelated fluoroquinolones 73–75

2.2.5 [h]-Annelated Fluoroquinolones

6-Oxo-6,9-dihydro[1,2,5]oxadiazolo[3,2-h]quinolin-7-carboxylic acid 76 was synthesized from 7-azido-8-nitroquinolone [231]. A convenient method for the synthesis of 6-oxothiazolo[3,4-h]quinolin-7-carboxylic acids 77 has been suggested (Scheme 35) [232]. The structure of compounds 76 and 77 has been confirmed by X-ray crystallography. Biological tests of fluoroquinolone 77 have revealed that this compound possesses a high activity against Gram-positive bacilli and staphylococci, including methicillin-resistant strains, as well as Gram-negative bacteria (Table 6).

Scheme 35

Structure of [h]-annelated fluoroquinolones 76, 77

Table 6 Activity of 77 (MIC, μg/ml)

A series of ethyl 2-R(Ar)-9-cyclopropyl-4-fluoro-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylates 78 have been obtained through cyclocondensations of the corresponding 7,8-diamino quinolones [233]. Also a number of tetracyclic [h]-annelated fluoroquinolones, such as 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-pyrido[2,3-a]carbazole-3-carboxylic acids 79 and their thiene isosters have been obtained (Scheme 36) [198]. All derivatives proved to possess a high activity against Bacillus subtilus and Staphylococci.

Scheme 36

Structure of [h]-annelated fluoroquinolones 78, 79

2.2.6 [i,j]-Annelated Fluoroquinolones

The most known representatives of tricyclic [i,j]-annelated fluoroquinolones are ofloxacin 80 and its analogues 81 (Scheme 37) [234]. Ofloxacin is well-known to clinical physicians, since more than 15 years it has been applied in medical practice. Ofloxacin has produced in two ready forms, peroral and injective ones, and both of them are characterized by a high clinical efficiency, wide range of indications for treatment, relative stability of the ofloxacin molecule in the process of bio-transformations in organism, and a low interference with drugs of other pharmacological groups. The oxygen atom in the oxazine ring is supposed to be an important element of the structure, thus providing an optimal antibacterial effect of this compound. Ofloxacin represents a racemic mixture of the right- and left-rotating optical isomers. The left-rotating enantiomer, levofloxacin, which proved to be much more active than its stereo analogue against nearly all bacteria, had been launched into medicinal practice in 1997. Inhibition of E. coli DNA gyrase by levofloxacin (I₅₀ 2,50 μg/ml) was shown to surpass inhibition of the same enzyme by ofloxacin (I₅₀ 6,20 μg/ml) [235].

Scheme 37

Structure tricyclic [i,j]-annelated fluoroquinolones

The starting materials 82 for the synthesis of ofloxacin and its analogues have been obtained by interacting ethyl 2-(tetrafluorobenzoyl)-3-ethoxy acrylates with 2-aminopropanol [236]. It is clear that use of optically active S-(-)-2-aminopropanol enables one to obtain levofloxacin [237–241]. Another approach to fluoroquinolones 81 is cyclization of compounds 83, derived from condensation of the corresponding benzoxa(thia)zines with diethylethoxy methylenemalonate (Scheme 38). In this way the synthesis of levofloxacin has been realized from the (S)-isomer of 7,8-difluoro-2,3-dihydro-3-methyl-4H[1, 4]benzoxazine [242].

Scheme 38

Synthesis of fluoroquinolones 81

During the last two decades the synthesis of levofloxacin and its S-(-)-pre-cursors has been improved considerably, and new approaches have been advanced [243–255]. In particular, kinetic resolution of 7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]-benzoxazine racemate using naproxen, N-[sulphonylsubstituted]-(R)-proline and (2S)-(6-methoxynapht-2-yl)propionyl chloride, has been advanced [256–261]. The optically active (S)-isomer obtained by this method has been used for the synthesis of levofloxacin (S)-(-)-80 [256]. Also a new synthetic approach to (S)-isomer through catalytic reduction of 7,8-difluoro-3-methyl-2H-1,4-benzoxazine with use of chiral Bronsted acids as catalyst and substituted dihydropyridine as a source of hydrogen has been described [262].

A number of ofloxacin analogues modified in position 10, including the well-known antibacterial drug pazufloxacin 84, have been synthesized [263–265]. Some compounds of this series show a high activity towards a number of microorganisms, such as Shigella flexneri, Proteus vulgaris [263]. It is worth noting that (3S)-10-[Cis-(3S,4S)-3-amino-4-(fluoromethyl)pyrrolidin-1-yl]-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazin-6-carboxylic acid 85 is more active than levofloxacin against Staphylococcus aureus 870307 [266]. An analogue of ofloxacin, containing a macrocyclic fragment in position 6 has been described [267]. All kinds of modifications of the structure of ofloxacin have been performed by varying substituents not only in positions 6 and 10, but also in the oxazine ring. In particular, compounds 86 show a comparable with ofloxacin activity against Gram-positive and negative microorganisms, and a high activity towards methicillin-resistant strain of S. aureus MR5867 [MIC 0,016–0,25 μg/ml for compound 86 (X = O, R = 3-cyclopropylaminomethyl-1-pyrrolidine)] (Scheme 39) [268].

Scheme 39

Structure of fluoroquinolones 84–86

Marbofloxacin 87 is a representative of another promising group of tricyclic fluoroquinolones, pyridino[3,2,1-i,j]-1,3,4-benzoxadiazines, is widely used in veterinary practice (Scheme 40) [269].

Scheme 40

Structure of fluoroquinolones 87–90

Synthetic methods to obtain other members of the family of [i,j]-annelated fluoroquinolones have been developed. For instance, derivatives of 1,3,4-thiadiazino[6,5,4-i,j]-, 1,3,4-oxadiazino[6,5,4-i,j]- and 1,2,4-triazino[5,6,1-i,j]-annelated quinolones 88a-c have been obtained by means of cyclization of 2-polyfluorobenzoyl acrylates bearing hydrazide, thiosemicarbazide or amidrazone moieties in position 3 [270–275]. Thiadiazino-fused quinolones 88a and compounds derived from displacement of fluorine atoms in positions 8 and 10 with cycloalkylimines are of great interest as promising compounds exhibiting not only antibacterial but also other types of biological activity [276, 277]. Synthesis of tetracyclic quinolones 89, in which the thiadiazine fragment is fused with both the pyridine and triazole rings has been described [278]. Activity of compounds 89 with R = H, Me against Gram-positive and Gram-negative bacteria is comparable with that of ofloxacin. Another core structure close to ofloxacin is 1,2,4-oxadiazino[i,j]-annelated fluoroquinolone 90 which was obtained by cyclization of 3-[1-(hydroxyiminoethyl)amino] acrylate [279]. The synthesis of tetracyclic fluoroquinolones 91 has been reported [280, 281]. The structure of novel pentacyclic fluoroquinolones 92 (Scheme 41), obtained by cyclization of ethyl 3-(benzazol-2-yl)hydrazino-2-polyfluorobenzoyl acrylates, was elucidated by X-ray crystallography [282–284].

Scheme 41

Structure of fluoroquinolones 91, 92

As a rule, cyclizations of 1-substituted 8-fluoroquinolones have an advantage in comparison with annelation of the pyridine ring to a benzazine moiety, thus allowing one to vary annelated fragments to a greater extent. However, the synthesis of levofloxacin is an exception, since the scheme suggesting to obtain first the optically active benzoxazine, as the key intermediate, followed by annelation of the pyridone fragment proved to be a more successful one.

2.2.7 Tetracyclic [a,i,j]-Annelated Fluoroquinolones

Several examples of tetracyclic [a,i,j]-annelated fluoroquinolones are available in the literature. In particular, compounds 93 and 94, bearing 3-aminopyrrolidine and (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane fragments, respectively are considered to be rather promising because they both exceed ofloxacin in antibacterial activity (Scheme 42) [285, 286].

Scheme 42

Structure of tetracyclic fluoroquinolones 93, 94

3 Other Types of Biological Activity of Fluoroquinolones

During the last decades compounds of the fluoroquinolone family proved to be not only effective inhibitors of bacterial enzymes; their antineoplastic [287], antiviral [41] (including concerning HIV [288]), anti-diabetic [289] and other types [290, 291] of biological activity have been intensively elucidated.

3.1 Anticancer Activity

Some representatives of the fluoroquinolone family, especially polycyclic compounds, are capable of inhibiting topoisomerase II, the key enzyme for replication DNA, and this is why they are promising for development of antineoplastic drugs [172, 292, 293]. In particular, a profound antineoplastic activity is demonstrated by quinobenzoxazines 95–97 (Scheme 43) [293–298]. Fluoroquinolone 95 (R’ = Н) is more active towards some tumor cells than such antineoplastic drugs, as adriamicin, camptotecin and etoposide [299]. Relationships between the nature of substituents in the amino fragment and the benzene ring of compounds 95–96 and their abilities to suppress the growth of tumor cells have been studied. Compounds with R’ = Н and R = Cl, NO₂ were shown to inhibit not only topoisomerase II, but also topoisomerase I [280, 299–301]. Amides 97 proved to suppress effectively the growth of HCT-116 cells, IC₅₀ values 0,03–0,4 μM [295].

Scheme 43

Structure of fluoroquinolones 95–97

Further steps to modify the structure quinobenzoxazines 95 involve annelation of the benzene rings to the benzoxazine fragment, as illustrated by the synthesis of benzo- and dibenzoderivatives 98 and 99 (Scheme 44) [299, 302]. Research studies on activity of pentacyclic derivatives 98 towards a number of tumor cells have shown that R-isomers are much more active, than S-isomers (Table 7). Also it has been revealed that a molecular target for fused fluoroquinolones 99 is the site of DNA capable of forming the quadruplex [303]. It has been shown that R-isomer 99 is characterized by a strong linkage with G-quadruplex and a low influence on topoisomerase II, while the S-isomer 99 has a strong linkage with topoizomerase II and a low interaction with G-quadruplex [296].

Scheme 44

Structure of fluoroquinolones 98, 99

Table 7 Inhibition of cancer cells by pentacyclic fluoroquinolones 98

The data of biological tests on activity of compound 100 (drug QQ58), as an intercalator of DNA [304] confirmed that this compound inhibits human telomerase (IC₅₀ 28 μМ); in organisms it is transformed into qarfloxacin which is linked with DNA G-quadruplexes [300, 304–306]. Polynuclear fluoroquinolones, containing the amide fragment, for example 101 (Scheme 45), have been shown to inhibit effectively the HeLa (mammalian cancer) growth (IC₅₀ 0,1–0,2 μМ) [303, 307, 308].

Scheme 45

Structure of fluoroquinolones 100, 101

Other fused fluoroquinolones, derivatives of benzazolotriazino[i,j]-annelated quinolon-6-carboxylic acids 92 have shown anticancer activity [309]. Biological tests on 9 types of tumors revealed that annelation of 1-methylbenzimidazo fragment to the triazine ring is more effective for suppression of cell growth, than that of the benzothiazole ring. An increase in numbers of fluorine atoms in the benzene rings of quinoline or benzazole fragments enhance antineoplastic action of pentacyclic derivatives; acids suppress growth of cells more strongly, than the corresponding ethyl esters. The biggest effect on melanoma has been observed in vivo experiments for fluoroquinolone 92d (Scheme 46, Fig. 2) [310].

Scheme 46

Structure of fused fluoroquinolones 92

Fig. 2

Cells growth suppression for derivatives 92а-d

Derivatives of levofloxacin 103 (Scheme 47), bearing in position 3 a lipophilic fragment, or the benzothiazole fragment instead of the carboxyl group, proved to exhibit antineoplastic activity (Table 8) [311]. The highest level of activity against glioblastoma has been observed for the ester 103а.

Scheme 47

Structure of fluoroquinolones 103–105

Table 8 Activity of levofloxacin derivatives 103 against some cancer cells

Antineoplastic activity of fluorine-containing derivatives of 1,3,4-oxa(thia)-diazine[6,5,4-i,j]quinolon-6-carboxylic acids 104, 105 has been studied on cultures of 60 lines of cancer cells for nine groups, such as leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, mammalian cancer [309, 310]. In the series of thiadiazinoquinolines the highest effect on antineoplastic activity gas been observed for compounds 105а and 105b bearing such pharmacophoric fragment, as N,N-dimethyl-1,3-diaminopropane. In case of compound 105b the full death of nearly all tumor cells MCF7 and SF-268 (more than 90 %) has been reached. Biological tests of compounds 105а,c,d,f have shown that the presence of a fluorine atom in position 8 facilitates suppression of cell growth. Also a high activity of compound 105а towards leukemia has been established [309, 310].

Not only [i,j]-annelated fluoroquinolones, but also polycyclic fluoroquinolones, in which an additional ring is annelated to [c]- or [h]-sides proved to possess antineoplastic action. Research studies on antineoplastic activity of 5-cyclopropyl-6,8-difluoro-7-(2,6-dimethyl-4-pyridinyl)-5H-pyrazolo[4,3-c]quinolin-3(2Н)-ones 106 have shown that derivatives containing the cyclohexyl group in position 2 are the most effective inhibitors of topoisomerase II of HeLa cells (mammalian cancer), while the dimethylaminocyclohexyl compound has shown the best data on cytotoxicity towards Р388 (leukemia) cells (Table 9) [312]. 6-Fluoro-4-oxopyridino[2,3-a]-carbazol-3-carboxylic acids 107 inhibit MCF-7 (breast cancer) and A549 (lung cancer), activity of 107b towards MCF-7 is twice higher, than that of ellipticine (Scheme 48) [198].

Table 9 Inhibitory and cytotoxicity properties of pyrazoloquinolones 106

Scheme 48

Structure of fluoroquinolones 106, 107

Also a number of bicyclic fluoroquinolones are capable of suppressing the growth of tumor cells. Incorporation of pyrrolo[2,1-c][1,4]benzodiazepine fragment in position 1 of fluoroquinolones resulted in compounds 108, which inhibit the growth of HT-29 (colon cancer) cells and А549 (lung cancer) up to 80 % [313]. Derivatives of 1-phenylsubstituted fluoroquinolones 109 suppress the growth of Solo205 (carcinoma) cells (IC₅₀ values 2–20 nМ) [314]. 3-Benzimidazolyl fluoroquinolone 110 and its analogues (Scheme 49), including [i,j]-oxazino annelated compounds, proved to suppress the growth of tumor KV, А2780 and Bel7404 cells [315].

Scheme 49

Structure of fluoroquinolones 108–110

Rather high antineoplastic activity of ciprofloxacin derivatives, containing a substituent in position 4 of the piperazine fragment has been shown [302]. Elucidation of the “structure-activity” relationships for 1-(2-thiazolyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylic acids has shown that several compounds of this series exhibit activity, comparable with the well-known drug etoposide [316–318]. Also the data on activity of amides of 7-substituted 1-(2-thia-zolyl)- and 1-(2-benzothiazolyl)-1,8-naphthyridin-4-on-3-carboxylic acids have been reported [319]. Ethyl 1-(4-cyano-2,3,5,6-tetrafluorophenyl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinolin-3-carboxylate proved to inhibit the phosphorylation process of transcription STAT3 activator that plays an important role for cancer therapy [320].

3.2 Tuberculostatic Activity

Being effective inhibitors of DNA-gyrase of mycobacteria some derivatives of fluoroquinolones are important for therapy of rifampicin-resistant tuberculosis [321]. In particular, values of minimum inhibitory concentrations against M. tuberculosis for a number of elucidated fluoroquinolones proved to be in the range from 0,12 to 128 μg/ml (Table 10) [322, 323].

Table 10 Tuberculostatic activity of some fluoroquinolones

An important synthetic approach for development of fluoroquinolones which are active against Mycobacterium tuberculosis appears to be introduction of isoniazide and pyrazinamide residues into the piperazine fragment in position 7. Indeed, 1-tert-butyl substituted fluoroquinolones 111 and 1-cyclopropyl-5-amino-fluoroquinolones 112 proved to exhibit a high activity towards Mycobacterium tuberculosis in vivo [38]. The minimum inhibitory concentration against M. tuberculosis H₃₇R_v for compound 113b is 0,78 μg/ml (Scheme 50) [324]. Also quinolones, bearing residues of hydrazides of substituted benzoic acids, which can be regarded as isosters of isoniazide, proved to be active compounds (MIC 0,5 μg/ml for multiresistant M. tuberculosis А8 241) [325].

Scheme 50

Structure of fluoroquinolones 111–113

1-Cyclopropyl-8-methoxyquinolones 114 are active against Mycobacterium tuberculosis, its multi-resistant strains, as well as Mycobacterium smegmatis [326]. Derivative 115 possesses tuberculostatic activity against Meningitis tuberculosis Н ₃₇ R _v (MIC 0,16–0,35 μg/ml) [327]. 1-[(6′-Fluoro-1′,4′-dihydro-7-(4”-methyl-1”-piperazinyl)-1′-ethyl-4′-oxo-3′-quinolylamido)-3-iminomethyl]-rifampicin 116 proved to exhibit a considerable tuberculostatic activity (Scheme 51) [328].

Scheme 51

Structure of fluoroquinolones 114–116

1-(4′-Amino-2′-fluoro)phenyl substituted fluoroquinolones 117 (R = H, Me) inhibit the growth of M. tuberculosis [329]. Incorporation of aminoester or polyethyleneamino fragments has been suggested to increase their ability to penetrate through cellular membranes. Indeed, fluoroquinolones 118 have been established to possess a high specific activity against mycobacteria and a low toxicity [330]. Tuberculostatic activity of derivatives 118 (R = H; X, Y = 0; n = 4) proved to be five times higher than that of pefloxacin (Scheme 52).

Scheme 52

Structure of compounds 117, 118

Several compounds [331] of the benzothiazolo[3,2-a]quinolone-6-carboxylic acids 119 family (Scheme 53) exhibit high tuberculostatic activity relative to multi-resistant strain of M. tuberculosis (Table 11).

Scheme 53

Structure of fluoroquinolones 119–121

Table 11 Tuberculostatic activity of fluoroquinolones 119

Ofloxacin and its analogs are promising drugs for tuberculosis treatment. Ofloxacin (daily dose 300–800 mg) and levofloxacin (250–500 mg a day) in combination with p-aminosalicylic acid, cycloserine, or ethionamid are effective for the treatment of multi-resistant strains of tuberculosis. On using of these fluoro-quinolones, a relatively high concentration in cells is reached, that increasing their antibacterial activity [38]. Derivatives of ofloxacin, containing the nitro group in position 8, e.g. 120 proved to possess a high tuberculostatic activity [332]. Also compounds showing tuberculostatic activity have been found among oxadiazino-quinolines 121 and thiadiazinoquinolines 105 (MIC 0,2–0,4 μg/ml) [276, 277].

3.3 Antiviral Activity

Fluoroquinolones 122, bearing the (triazolylmethyl)phenyl fragment in position 1 and an aryl substituent in position 4 of piperazine, are capable of protecting the HIV-infected cells from a virus-induced destruction (IC₅₀ 0,25–0,7 μМ). They appear to be a new structural type of effective drugs for treatment and prevention of viral diseases caused by HIV retroviruses [333]. Fluoroquinolones 123 with 4-(2′-pyridinyl)-1-piperazine fragment in position 7, inhibit reverse transcriptase of HIV-1 [334]. 8-Difluoromethoxy- and 8-trifluoromethylcarboxylic acids 124 inhibit replication of HIV-1, while CF₃- derivatives are more active against HIV-1 than the corresponding difluoromethoxy compounds (Scheme 54, Table 12) [335–338].

Scheme 54

Structure of fluoroquinolones 122–124

Table 12 Inhibition of HIV-1 by 124

[i,j]-Annelation of the oxazine ring is favorable for exhibiting of antiviral activity, but does not lead to such promising compounds, as 8-methoxy- and difluoro-methoxy derivatives [339]. Fluoroquinolone 125c is more active against the virus HIV-1, than thiazeto derivative 126 [336]. Values IC₅₀ 3,7 μМ for 125а and 1,7 μМ for 125b have been found, while values EC₅₀ 0,074 μg/ml for 125c and 0,4 μg/ml for 126 have been obtained. Also a number of tricyclic fluoroquinolones 127 proved to possess a high activity (ЕС₅₀ 0,008−2.3 μg/ml) (Scheme 55) [340]. Also effective compounds against HIV-1 have been discovered in the series of the Mannich bases of norfloxacin [341].

Scheme 55

Structure of fluoroquinolones 125–127

Fluoroquinolone 128 bearing the (2-hydroxyethoxy)methyl fragment at N-1 is active against herpes virus HSV-1 (EC₅₀ 2,30 μМ), however the level of its activity is lower than that of acyclovir (EC₅₀ 1,09 μМ) [41]. 8-Trifluoro-methylquinolones 124 have been reported to suppress human cytomegalovirus [342]. Fluoroquinolones 129, containing the sulphamidomethyl group in a piperazine fragment, are active against influenza H1N1, H3N2 and H5N1 viruses [343]. Tricyclic fluoroquinolones 130, 131 were found to possess a high activity against hepatitus B virus (IC₅₀ 0,1 μМ) (Scheme 56) [344, 345]. Ciprofloxacin and levofloxacin are recommended for treatment of patients after transplantation surgery operations in order to prevent the disease caused by poliomavirus BK [346].

Scheme 56

Structure of fluoroquinolones 128–131

3.4 Other Types of Biological Activity

Some fluoroquinolones appear to be active against fungi and parasites. For instance, the Mannich derivatives of norfloxacin 132 demonstrate a considerable antifungal activity against Histoplasma capsulatum. One of compounds of this family is more active than clotrimazole towards Microsporum audouinii, while other derivatives surpass clotrimazole in relation to Cryptococcus neoformans or Microsporum gypsum. From all derivatives 132 which have been studied (Scheme 57), compound with R = Br, X = N, R¹ = NH₂, Y-Z = CH, A = COMe, R2-R3 = OMe proved to exhibit the highest antifungal activity (MIC for Cryptococcus neoformans and Microsporum audouinii 0,6 μg/ml) [341].

Scheme 57

Structure of fluoroquinolones 132

Moxifloxacin, gatifloxacin, trovafloxacin, and grepafloxacin belong to a new generation of fluoroquinlones, showing anti-parasitic activity against Toxoplasma gondii and Plasmodium falciparum which cause such severe diseases as toxoplasmosis and malaria, respectively. These fluoroquinolones are targeting at the DNA-gyrase, located in a top layer of parasites [347]. For example, the IC₅₀ value for trovafloxacin against Toxoplasma gondii is 0,96 μM. The data on activity of fluoroquinolones 133 against parasites (Coccidia) [348], and activity of 7-(3′-azabicyclo[3.1.0]hexyl)quinolones 134 in relation to plasmodium have recently been reported (Scheme 58) [149].

Scheme 58

Structure of fluoroquinolones 133–135

Some fluoroquinolones have been shown to exhibit cardiovascular, hypertensive, and antitrombocyte activities. For instance, compound 135 inhibits aggregation of trombocytes [349]. According to the recently published data, 5-amonofluoroquinolones 136 and 137 are active as glicogensyntase-kinase-3β inhibitors (GSK, serine-treonine-proteinkinase) [265]. Bi- and tricyclic fluoroquinolones, bearing the fragment of N-(2-pyridinyl)ethylenediamine appear to be promising GSK inhibitors (Table 13) [265]. 138, their 8-fluoro- and 5,8-difluoroderivatives proved to be selective allosteric modulators of М1 receptor, activation of which is important for therapy of the Alzheimer’s disease (Scheme 59) [350–353].

Table 13 Inhibition of GSK by fluoroquinolones 136, 137

Scheme 59

Structure of fluoroquinolones 136–138

4 Structure and Spectral Characteristics

The structure of fluoroquinolones has been elucidated in crystals and solutions. The data on X-ray crystallography analysis of fluoroquinolines are available in the literature for both quinolones [89, 123, 354, 355], and their polycyclic [204, 231, 232, 270, 271, 282, 283, 356] condensed systems.

The ¹Н, ¹³С and ¹⁹ F NMR spectra for the series of fluoroquinolines have been registered and analyzed. ¹Н, ¹³С NMR spectra of fluoroquinolones bearing rather complicated optically active fragments, including heteronuclear correlation experiments, have been discussed in the literature [164–168]. Elucidation of NMR ¹⁹ F spectra of compounds 12 has revealed long-range coupling constants ⁷ J _F-F between the trifluoromethyl group and fluorine atom in position 8, which are realized through space due to vicinity of interacting spins [39]. The ¹⁹ F NMR spectra of benzimidazo [2′,3′:3,4]-1,2,4-triazino[5,6,1-i,j]quinoline ring system 92 demonstrate unusual through space ¹H-¹⁹ F and ¹⁹ F-¹⁹ F spin-spin interactions with coupling constants ⁷ J(F¹, F¹¹) = 3.5–4.0 Hz and ⁶ J(F¹, Н¹²) = 2.0–3.0 Hz (Scheme 60) [284].

Scheme 60

Long-range coupling constants in compounds 12, 92

5 Complexes of Fluoroquinolones with Metals

Due to the presence of the carboxyl and β − oxo groups, as well as azaheterocyclic fragments, fluoroquinolones have a profound ability to form metal-chelates, and other ionic structures. It is known that complexes with metals may enhance activity of fluoroquinolones due to a better solubility and endocellular accumulation [357, 358]. The crystal structures of a number of metal complexes, results of their thermal analysis, IR and NMR spectra of complexes and their bioactivity have been considered [359]. In the recently published review article [360] the data concerning the structure and properties of metal complexes of fluoroquinolones, and their interaction with DNA have been analyzed. Also physical and chemical characteristics, as well as pharmacokinetic data and antibacterial properties of fluoroquinolones complexes with a variety of metals have been reviewed [361].

The Cu(II)-complex of ciprofloxacin was shown to possess a high activity against Mycobacterium tuberculosis than the parent compound [362]. An enhanced solubility of metal complexes in lipids facilitates their transport into bacteria cells, while an easily proceeding reduction of metal leads to the formation of Cu(I) and activation of oxygen which kills mycobacteria. Authors came to a conclusion that redox-active metal complexes are very promising compounds for development of highly active antitubercular drugs. Indeed, the minimum inhibitory concentration for enrofloxacin complex Cu(erx)₂(H₂O) against E. coli и P. aeruginosa is 0.125 μg/ml, while the same index for the parent enrofloxacin is 1.0 μg/ml [363]. Antibacterial activity of N-propyl norfloxacin (pr-norf) complex with CuCl₂ and phenanthroline (phen) [Cu(pr-norf)(phen)Cl] has been was reported [364]. For instance, the formation of sparfloxacin (sflx) (Scheme 61) dimeric complex with Cu(II) [Cu₂(sflx)₂] and mononuclear complex with phenanthroline [Cu(phen)(sflx)H₂O] has been shown (Figs. 3 and 4) [365].

Scheme 61

Structure of sparfloxacin (sflx)

Fig. 3

Structure of complex Cu₂(sflx)₂ (Reproduced with permission of Elsevier [365])

Fig. 4

Structure of complex Cu(phen)(sflx)H₂O (Reproduced with permission of Elsevier [365])

Antiproliferative effect of sparfloxacin and its metal complexes against hormone independent BT20 breast cancer cell line has been studied (Fig. 5) [365]. Coordination of sparfloxacin with copper in the form of dimeric complex Cu₂(sflx)₂ has been established to diminish the value of inhibitor concentration IC₅₀ (μΜ) in approximately ten times. These data are in agreement with a hypothesis that biological activity of fluoroquinolones is in many respects caused by their ability for metal chelate formation. Antitumor activity of moxifloxacin-copper complexes against breast cancer cell lines has also been described [366].

Fig. 5

Suppression of cells growth by sparfloxacin and its metal complexes, a- spfx, b-Cu₂(sflx)₂, c-[Cu(bpy)(sflx)H₂O], d-[Cu(phen)(sflx)H₂O], e-[Cu(df)(sflx)H₂O]; bpy = bipyridine, phen = phenanthroline, df = 4,5-diazafluoren-9-one (Reproduced with permission of Elsevier [365])

Complex of norfloxacin [Fe(nf)₂(H₂O)₂]Cl₃ · 6H₂O was shown to exhibit a higher antibacterial activity than the parent norfloxacin against E. coli and Bacillus dysenteriae bacteria [367]. Also it is worth noting that antimicrobial activity of cobalt complexes of ciprofloxacin is less, than that of copper complexes [368].

The reaction of ciprofloxacin (cfH) with metal salts in the presence of aromatic polycarboxylate ligands (or under basic conditions) has been found to give original metal–cfH complexes, for example, [Ba₂(cf)₂(1,4-bdc)(H₂O)₂]∙H₂O and [Mn(cfH)(1,3-bdc)] (bdc = benzenedicarboxylate). The structure of [Ba₂(cf)₂(1,4-bdc)(H₂O)₂]∙ H₂O consists of unique two-dimensional arm-shaped layers (Fig. 6), while the second complex contains double-chain-like ribbons constructed from [Mn₂(cfH)₂(CO₂)₂] dimers and 1,3-bdc (Fig. 7) [369].

Fig. 6

Structure of complex [Ba₂(cf)₂(1,4-bdc)(H₂O)₂]∙H₂O (Reproduced with permission of Wiley [369])

Fig. 7

Structure of complex, [Mn(cf)(1,3-bdc)] (Reproduced with permission of Wiley [369])

Supramolecular structure of cadmium complexes of ciprofloxacin [Cd₂(cf)₂(bptc)(H₂O)₂]∙8H₂O is shown in Fig. 8 [369]. Two units are connected together by μ₃-O atoms of carboxylic groups from cf ligands in an edge-sharing mode to form [M₂(cfH)₂(H₂O)₂] dimers.

Fig. 8

Supramolecular structure of ciprofloxacin complex, [Cd₂(cf)₂(bptc)(H₂O)₂]∙8H₂O (bptc = 3,3′,4,4′-benzophenontetracarboxylate) (Reproduced with permission of Wiley [369])

Complexes of norfloxacin with zinc(II), such as [Zn(nf)₂] · 4H₂O and [Zn(H₂O)₂(nf)₂](NO₃)_2, were found to exhibit a strong blue fluorescent emission [370]. The complex of Zn(II) with enrofloxacin and pyridine, as the second N-donative ligand, [Zn(erx)₂(py)₂] · 6H₂O · MeOH has been obtained (Fig. 9). Such complexes were found to interact with CT-DNA, thus demonstrating their ability to bind with DNA. According to the data obtained by using the UV spectroscopic titration technique, the binding strength for Zn(orx)₂(py)₂ corresponds to the highest K _b value [371].

Fig. 9

Structure of complex [Zn(erx)₂(py)₂] · 6H₂O · MeOH (Reproduced with permission of Elsevier [371])

The formation of ofloxacin complexes with magnesium has been studied by using NMR ¹Н and 2D ¹H-¹³C HSQC methods [372]. Behavior of coordinative compounds of ciprofloxacin, levofloxacin and lomefloxacin with Al(III) in water solutions has been elucidated by NMR ¹Н and ¹³С spectroscopy [373]. Tetrakis[4-(3-carboxy-1-ethyl-6-fluoro-4-hydroxonio-1,4-dihydro-7-quinolyl)-1-methyl-piperazin-1-ium] di-μ₂-chlorido-bis[tetrachloridobismuthate(III)] tetrachloride octahydrate, (C₁₇H₂₂FN₃O₃)₄[Bi₂Cl₁₀]Cl₄ · 8H₂O, is composed of edge-shared centrosymmetric dinuclear [Bi₂Cl₁₀]⁴⁻anions, Cl⁻anions, dihydrogen pefloxacinium cations and water molecules. The Bi^III coordination polyhedron is a distorted octahedron [374].

One of the modern trend in the chemistry of fluoroquinolones is the formation of Pd(II) and Pt(II) complexes with a number of fluoroquinolones, such as ciprofloxacin, levofloxacin, ofloxacin, sparfloxacin and gatifloxacin [375, 376]. Two examples are given below Scheme 62.

Scheme 62

Pd(II) and Pt(II) complexes of fluoroquinolones

A great deal of complexes derived from enoxacin, norfloxacin, lomefloxacin, fleroxacin, ofloxacin, rufloxacin, gatifloxacin and sparfloxacin and their luminescence properties of Tb³⁺– and Eu³⁺–complexes have been investigated (Fig. 10) [377]. Complexes of Tb³⁺–enoxacin, Tb³⁺–norfloxacin, Tb³⁺– lomefloxacin and Tb³⁺–fleroxacin were shown to display a relatively strong emission intensity compared with Tb³⁺–ofloxacin, Tb³⁺–rufloxacin, Tb³⁺–gatifloxacin and Tb³⁺– sparfloxacin. Quite weak peaks with unique characters of Eu³⁺ at 590 and 617 nm have been observed in the luminescence spectra of Eu³⁺–enoxacin, however no luminescence of Eu³⁺ could be detected when Eu³⁺ was added to other fluoroquinolones. The distinct changes in emission intensities for Tb³⁺–fluoroquinolone and Eu³⁺–fluoroquinolone complexes might originate from different energy gaps between the triplet levels of fluoroquinolones and the excited levels of Ln³⁺. Thus, research studies in the field of complexes of fluoroquinolones with metals are aimed at obtaining of biologically active coordination compounds, and also to use of complex formation for quantitative analysis of fluoroquinolones.

Fig. 10

Emission spectra of Tb³⁺–complexes of some fluoroquinolones (Reproduced with permission of Elsevier [377])

In conclusion it is worth noting that despite the successes reached in area of synthesis, studying of biological activity and application of fluoroquinolones, tasks of design of new structures, development of synthetic approaches, modifications of existing drugs by means of incorporation of substituents into positions 1–8 as well as annelation of additional rings to quinolone fragment continue to remain actual. Not less important studying of structure–activity relations among fluoroquinolones as in process of accumulation of such material all new dependences of antibacterial activity on positions and the nature of the substituents in a fluoroquinolone fragment become clear. The increasing attention is given to the synthesis of optically active isomers among fluoroquinolones and to their use as medicines. Fluoroquinolones are known to be not only antibacterial drugs, but also as compounds exhibiting other types of biological activity. Development of novel anticancer and antiviral agents in the series of fluoroquinolones is in progress. Researches in the field of metalocomplexes of fluoroquinolonecarboxylic acids directed to elucidation of “structure – bioactivity” relations and cation roles in interaction of fluoroquinolones with DNA are developed. Studying of complex formation of fluoroquinolones plays a crucial role for obtaining the fullest data on pharmacokinetic interaction of fluoroquinolones with other drugs.