Quinoline scaffold as a privileged substructure in ... scaffold as a privileged substructure in antimicrobial drugs ... Drug design is a complex issue that still lack ... Fig. 1 Quinine

Quinoline scaffold as a privileged substructure in antimicrobial drugs

R. Musiol, T. Magdziarz and A. Kurczyk

Institute of Chemistry, University of Silesia, Szkolna 9, 40-007, Katowice, Poland

Drug design is a complex issue that still lack general approach with proven reliability. Combinatorial chemistry and HTS techniques did not appear to be effort-effective. As an alternative we have the fragment based design and more recently so called the privileged structures approach. We believe that some structural subunits are especially effective in design of bioeffectors. However it is not clear what makes one molecular scaffold more privileged than another. Overall frequency of appearance of molecular scaffold in bioactive compounds or natural substances may be used as a good factor of qualitative discriminator of privileged structures. According this, the quinoline scaffold, due to its frequent appearance in bioactive substances can be regarded as a privileged structure. It is abundant in number of natural compounds such as alkaloids: quinine, camptothecin or cinchonidine. In synthetic medicinal chemistry the quinoline motif is widely exploited revealing a spectrum of activity covering anticancer, antifungal, antibacterial and antiprotozoic effects. In fact, introducing chloroquine into treatment of malaria more than 60 years ago triggered a new era of quickly developing antimicrobial drugs through nalidixic acid and fluoroquinolones. In this review we wish to explore antimicrobial quinolines as an important class of drugs from both natural and synthetic sources.

Keywords quinoline, privileged structure, antibiotics, fluoroquinolones

1. Privileged structures

In 1990 Johnson and Maggiora formulated the similarity principle, which states that structurally related compounds display similar biological activity [1]. Although multiple exceptions to this theory are known, this essential rule still underlies the art of molecular design. Moreover, in some cases it is feasible to identify common molecular fragments, so-called privileged motifs, which ease ligand binding to an individual receptor or particular receptor family. The term privileged structures was first introduced in 1988 by Evans and co-workers in their search for cholecystokinin (CCK-A) receptor antagonists derived from the natural product asperlicin and was defined as “a single molecular framework able to provide ligands for diverse receptors” [2]. Later this definition was updated by Patchett and Nargund [3]. Since then, several reviews deal with the concept of privileged motifs [4-9] and numerous molecular fragments have been described as privileged, e.g. benzazepinone [3], diphenylmethane [3], benzylpiperidine [3], biphenyltetrazole [3], indole [3,10], biphenyl [3,11], spiroindoline sulfonamide [3,12], spiroindanyl piperidine [12], 1,4-dihydropyridine [13], 2,6-dichloro-9-thiabicyclo[3.3.1]nonane [14] and benzopyran [15,16]. Although privileged substructures are intended to be target class-specific it has been shown that this separated molecular subunits also appeared in compounds active against other target families [17]. Furthermore, a single particular structural subunit time and again could be present in thousands substances including various natural products exhibiting miscellaneous pharmacological activities. From beginning to date, the original concept definition has evolved in most cases to describe not only those structures which ease ligand binding to an individual receptor or particular receptor family, but also those that modulate proteins lacking a strict target class relation. For example, this is the case for two heterocyclic motifs, namely quinoline and acridine, which are particularly frequent in compounds active against quite different pathologies [18]. Those kinds of privileged molecular fragments can thus be considered as generic drug-like motifs. However, privileged structures should not be confused with promiscuous aggregators, which unspecific behavior is caused by the tendency to self-associate into colloids [19]. To sum up, a privileged motif is a substructure of a molecule which itself represents the superstructure and this specific determined molecular subunit can be utilized as a template for the design of therapeutics with high affinity and specificity for a broad range of protein targets. Privileged scaffolds might be successfully applied in the drug discovery process, e.g. as core structures for synthesis [20] and optimal starting points for the library design [21] of ligands with affinity to certain molecular targets. There are several examples of privileged scaffold library synthesis: libraries based on a 2-arylindole scaffold resulted in the discovery of potent ligands for a variety of G-protein coupled receptors [22], synthesis of purine derivatives [23], a library of tetrahydro-1,4-pyrazolodiazepin-8(2H)-ones [24]. These examples indicate that the privileged structure concept has emerged as a successful approach to the discovery of novel biologically active molecules. In addition, privileged structures typically exhibit good drug-like properties, which in turn lead to more drug-like compound libraries and leads. The application of the privileged structure approach, both in traditional medicinal chemistry and in the design of focused libraries, was widely discussed in the literature [4]. On the other hand, many of the new medicines approved in the last years are in fact only small modifications of existing marketed drugs. In no doubt, this is a direct impact of implementing similarity approaches in the drug discovery. However, this is not the only reason. It seems that the drug development process highly depends on industrial and state regulations. Every new medicine has to conform with very strict requirements. To satisfy those high standards

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and to introduce a new drug to the market it is more convenient to chose as a starting material a structure of known drug or any compound that has already passed some of the requirements. One cannot forget there is also an economical factor and as well as liability issues. The utilization of structures of already known drugs in the development of new medicines can significantly lower the cost of the pharmaceutical innovation [25]. It seems also that this approach is very attractive for the industry, since it reduces the risk of pharmaceutical liability. In turn, all described reasons have somehow inspired efforts to invent new and completely different methods as a source of structurally distinctive compounds with desired pharmacological actions, e.g. scaffold hopping concept [26]. As opposed to privileged motifs, the main goal of the scaffold hopping techniques is to find structurally novel compounds by modifying the central core structure of the molecule and yet binding to the same molecular target. One should bear in mind that a privileged molecular fragment is a substructure of a molecule, which only in general defines the pharmacological manners of a compound but alone does not automatically induce a preferred bioactivity. In other words, the presence of a privileged scaffold in a molecule does not explicitly identify the target receptor and desired binding behavior. The question which still remains is how to discover new privileged scaffolds? There are two possible scientific strategies in search for new privileged motifs: experimental or computational methods. The former was employed in one of the statistical analysis of NMR-derived binding data indicated that compounds which contain a biphenyl substructure preferentially bind to a wide range of proteins [11]. The latter are mainly based on data extracted from structural chemical databases and analyzed during the mining process. Those kind of computational investigations have exposed that the diversity of shapes in the set of known drugs is extremely low. The undeniable proof was revealed by Bemis and Murcko, who analyzed the common structural features present in commercially available drugs. The key finding of an investigation maintains that the shapes of half of the drugs in the database have been described by the 32 most frequently occurring frameworks [27]. Furthermore, based on data retrieved from the BindingDB database, there was conducted a systematic and comprehensive computational selectivity-centric analysis of public domain target-ligand interactions. In consequence, more than 200 molecular scaffolds were identified that are selective for individual targets among closely related ones, and a majority of these scaffolds yields compounds that display a target-selective tendency. These scaffolds are also underrepresented in approved drugs, what was revealed [28]. Consequently, frequency of occurrences of that kind generic drug-like molecular fragment among drug populations and bioactive compounds ensembles could be a valuable index of the privileged structures estimation. A variety of other distinctive strategies and approaches have been implemented to designate privileged substructures. Most of them are based on database mining and a variety of fragmentation algorithms [29]. In other study, biologically privileged motifs have been identified for specific therapeutic classes using a retrosynthetic analysis [30]. Analyzing molecular and structural chemical databases and some literature data [18] we indicated quinoline as a probable privileged structure. Quinolone antibiotics constructed of the quinoline ring system can be here the most spectacular example of the potential efficiency of this system in medicinal chemistry [31] while a quinine molecule that also contains a quinoline moiety proves the Nature preference for the system. The quinoline scaffold can also be found in many classes of other biologically active compounds used as antifungals, antibacterials, and antiprotozoic drugs [32]. Here we present only the very initial results of chemical database mining in order to evaluate a frequency of occurrences of two heterocyclic isomeric molecular fragments, namely quinole and isoquinoline. The comparison of the Beilstein (B) and DrugBank (D) database hits of quinoline and isoquinoline fragment containing molecules clearly suggests that it is not necessarily synthetic availability of the quinoline system that makes this system more popular than the isoquinoline one [33]. This seems to clearly indicate that the quinoline is overrepresented in the drug population more often than isoquinoline one. Is it however just polypharmacological profits of quinoline that decides the advantages of this scaffold over isoquinoline? These initial findings forced us to conduct a comprehensive investigation of the quinoline scaffold to designate privileged structural antimicrobial drug architecture.

2. Quinoline antimicrobials of natural origin

Abundance of natural substances suitable to trigger biological response has been one of indispensable parts of our environment for centuries. It is trivial to say that our ancestors owe most of their drugs to the Nature. However it may be surprisingly that in spite of the technology still roughly half of our pharmaceuticals have natural provenience [34,35]. Overall rank of the appearance of new natural drugs has considerably lowered with the time in advantage of semi-synthetic or synthetic drugs. With the era of the combinatorial chemistry and high throughput screening the rate of natural products introduced to the market decreased even further. Nowadays, when this approach did not fully meet our – in fact high – expectations we turned again to the Nature as a source of new drugs [36-38]. However we search rather for inspiration (leading structures) than for ready-to-use solutions [39,40]. Probably the most important quinoline related alkaloid used broadly for its antimicrobial potency is quinine (Fig 1) [41]. Extracts from the bark of cinchona trees was used by Peruvian Indians Quechua as remedy for fever. This method of use was then introduced in Europe by Jesuits as early as in 17 century. From that time it still in use to treat malaria

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and muscle cramps [42,43]. Exact mechanism of action of quinine is not fully understood yet but believed to inhibit heme polymerase leading to death of malaria parasites.

O

N

HOHH

N

H

H

Quinine

O

N

H OHH

N

H

H

Quindine

H

OH

N+ O

O

OH

Pteleatine

N

O

OO

Cusparine

NH

O

O

O

OH

O

Yaequinolone J2

N O

O

O

O

OH

OH

Kolbisine

Fig. 1 Quinine and some furoquinolines from natural sources. The importance of quinine was especially apparent during colonization times or World War II and triggers the continuous search for alternative sources of the drug. Despite several attempts to synthesize [44,45], the extraction from cinchona bark remains the only economical process of production of thousand tons of quinine today. Although the major part is nowadays consumed in beverages as tonic water. With this in mind quinine can be considered as great lesson we have got from the Nature and we are still learning of its use by modifying the quinoline skeleton. Cinchona tree is one of many plants rich in quinoline related alkaloids that have been found useful in diverse medical treatment. Large number of potentially interesting plants were selected for antimicrobial activity in almost every part of the world [38,46-48]. Rutaceae family is an especially well investigated group of plants hiding many interesting alkaloids of whom more than 50 are known for structure and antimicrobial activity [49]. The presence of some specific quinoline alkaloids in plants from genera of Rutaceae family is so significant that can be used as markers for chemosytematic or taxonomic assignments [50]. Noticeably small quinoline derivatives, namely furoquinolines (Fig 1), quinolones (Fig 2), are the most common metabolites in Rutaceous plants (Table 1). The spectrum of activity of the rutaceous alkaloids is broad and covers antileishmanial (mainly simple quinoline and 2-alkylquinolines), antibacterial (in furoquinoline group) and antifungal (quinolones) activity. Kolbisine and pteleatine shown on Fig 1 and Table 1 are members of furoquinolines – a class of antimicrobially active alkaloids. Along with skimmianine, kokusaginine, maculine they are present in a large number of rutaceous plants as Galipea and Esenbeckia. The broad spectrum of activity of furoquinolines encloses also alzheimer [51-54] and anticancer [55] properties. The mechanism of antimicrobial activity of furoquinolines was connected to their ability to bind DNA [56]. Structure of 13 diferent furoquinolines related to skimmianine isolated from Teclea nobilis plant used by Maasai tribes of Sekenani Valley to treat malaria [57] were described [58]. Such diversity of bioactive substances in extracts form leaves of one plant only speaks for the idea of exploring the traditional way of use medicinal plants. As seen in Table 1 quinolone related alkaloids are present in wide variety of sources not restricted to Rutaceae family only. This important class of compounds have been explored for more than 20 years [83,84]. Yaequinolone and megistoquinones are among them especially interesting for potent antibacterial activity and strong similarity to quinolinodiones (Fig 2).

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Table 1 Some of the naturally occurring quinolines with antimicrobial activity.

Structure Name Source* Biological activity Ref

N1

2

3

45

6

7

8

2-propyl; 4-OMe Chimanine A Galipea longiflora (Rutaceae family)

Leishaniasis [59-61]

2-(1-propenyl) Chimanine B Galipea longiflora Leishaniasis [59-61] 2-(3-methyloxiranyl) Chimanine D Galipea longiflora Leishaniasis [59-61] Other 2-alkyl drivatives Galipea longiflora Leishaniasis [59-61]

4-CN Xylaria sp. BCC 9653 (wood decaying fungi)

Antimycobaterial [62]

6-OH; 8-COOH Cortinarius subtortus Antifungal [63]

N O1

45

6

7

8

2'

3'

4,7,8-OMe Skimmianine Galipea longiflora Leishmaniosa, Anticholinesterasic

[52,59,60]

4,6,7-OMe Kokusaginine Galipea longiflora Leishmaniosa, Anticholinesterasic

[52,59,60]

4-OMe; 6,7-methylenedioxy

Maculine Esenbeckia leiocarpia Teclea afzelii (Rutaceae)

Antiplasmodial [52,64,65]

4,8-OMe; 6,7-methylenedioxy

Flindersiamine Esenbeckia yaaxhokob (Rutaceae) Antibacterial, antimalarial

[66-68]

4-OMe; 5-CH2CH=CMe2; 6,7-methylenedioxy; 8-OH

Tecleaverdoornine Teclea verdoorniana (Rutaceae)

Antiplasmodial [52,53] [64,69]

Fig 1 Pteleatine Ptelea trifoliate Hpotree (Rutaceae)

Antibacterial, antimycobaterial

[70]

4,8-OMe g-Fagarine Esenbeckia febrifuga (Rutaceae) Antiplasmodial [54]

4-OMe Dictamine Esenbeckia febrifuga, Almeidea coerulea (Rutaceae)

Antiplasmodial, antifungal

[54,65]

4,8-OMe;7-OH Haplopine Dictamnus dasycarpus Turcz. (Rutaceae)

Antifungal [71]

Fig 1 Kolbisine Teclea afzelii (Rutaceae) Antibacetrial, antifungal

[51]

N

O

R

R=H; 2-nonyl Ruta graveolens (Rutaceae) Antifungal [72]

Fig 3 Aurachin C Stigmatella aurantiaca (Myxobacteriae) Rhodococcus erythropolis (bacteria)

Antifungal, antibacterial

[73-76]

Fig 3 Aurachin D Stigmatella aurantiaca (Myxobacteriae)

Antifungal, antibacterial

[73-76]

Quinolones; R=H, Me; n-0,1,2,3… Fig2

Rutaceae gen. Broad antifungal antibacterial Antimycobacterial

[72,77,78]

R=H; 2-tridec-8-en-1-yl Evocarpine Evodia rutaecarpa (Rutaceae) Antimycobacterial [78]

Fig 1 Cusparine Galipea longiflora (Rutaceae) Leishmaniosa, Trypanosomiasis (Chagas sickness)

[59,60]

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N O

R

R=H; 4,8-OMe Edulitine Casimiroa edulis (Rutaceae) Antibacterial [79]

Fig 1 Yaequinolone Penicilinum sp Antibiotic Insecticidal

[49,80,81]

Fig 2 Megistoquinone Sarcomelicope megistophylla (Rutaceae) Streptomyces spp

Antibacterial [82]

*only one or two more important sources given, further can be found in references. Streptomyces genus is known for the largest production of antimicrobial agents. Among them structures of lavendamycine, streptonigrin (Fig 2) and streptonigrone may be recalled as quinoline bearing compounds with broad antimicrobial activity [85-87]. Although the cytotoxicity of the alkaloids from this class were too high to safe use as antimicrobials they were extensively studied for their anticancer and antiviral activity [88,89]. Kurosawa et al reported a comprehensive case study on isolation, purification and determination of structure and antimicrobial activity of two depsipeptides from fermented broth of Streptomyces spp. [90]. Another antimiocrobially active quinolones were found in bark of Hartley (Sarcomelicope megistophylla) endemic plant form New Caledonia (Fig 2) [82].

NH

(CH2)n

O

O

Oquinolones (Rutaceae)

N

O

O

O O

O

NH

O

O

O O

O

O

Megistoquinone I Megistoquinone II

NN

NH

OH

O

O

O

NH2

NN

OH

O

O

O

NH2

OH

O

O

NH2

O

StreptonigrinLavendamycin

Fig. 2 Quinolones important class of quinoline related antibiotics. Hofle et al describes aurachins – an interesting group of compounds with antimicrobial activity isolated form bacterial strains as Myxobacterium (Stigmatella aurantiaca) or Rhodococcus (R. erythropolis) (Fig 3) [73-76]. These compounds are active against pathogenic fungi, inhibit photosynthesis and even show antibacterial activity against grampositive and gramnegative bacteria.

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Fig. 3 Aurachins antimicrobials isolated from Myxobacterium.

Undoubtedly natural sources of bioactive alkaloids for their scale and versatility remain untapped pipeline of new drugs. Naturally occurring antimicrobials have great potential of usefulness not only for their effectiveness. Their mechanisms of action however often unknown are intrinsically complex and multiaspect unlike to the lab-designed drugs. Side effects and unwanted activity are frequently smaller while pharmacokinetic is relatively good. Plant derived drugs are more biofriendly and “suited” to our system. Thus more and more research on natural antimicrobials can be anticipated. With appropriate screening systems based on the specificity of natural sources, tested diseases (organisms), and bioassays this can be cause of the near future [91].

3. Synthetic quinoline antimicrobials

Poor synthetic availability of quinine was main trigger of the intensive research for its alternatives. History of the first synthesis quinoline antimicrobials reach the time of First World War and diminishing of the availability of natural sources of antimalarial drug of great importance for military operations. After the war in Germany quinacrine was discovered – an acridine related potent antimicrobial agent. The Germany company Bayer was the only provider of quinacrine thus when the Second World War broken out USA was in great need for alternative drug. As shown in Fig 4 this lead to the discovery of chloroquine - the superior analogue of quinacrine [92]. It is noteworthy that both of the drugs are still in use for the malaria treatment [93,94]. At first the success of chloroquine resulted in enthusiastic abuse of chloroquine along with insecticides and declaration of the end of malaria. Few years later emergence of quickly spreading resistance resulted with apparent useless of chloroquine in several part of the world [95-97]. Another bud from the research on quinine alternatives become mefloquine. However its utility for prevent and treatment of malaria is high mefloquine has also some severe side effects that diminished its use [92,95]. Continuous treatment with mefloquine may lead to specific neuropsychiatric effects – very rare but, as well as, very dangerous [98-100].

N+

O

O-

Aurachin A

Aurachin P

N+

O

O-

OHOH

ON

O

OOH

N

Camptothecin

N

O

R

Aurachin C; R=OH

Aurachin D; R=H

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N

NH

N

O

Cl

Quinacrine

Cl N

NH

N

Chloroquine

O

N

HOHH

N

H

H

Quinine

FF

F

N

F

FF

H OHH

NH

Mefloquine

O

N N

O

OH

Nalidixic acid

NH

O

OH

O

F

R

R

R

Fluoroquinolones

N

NH

NH2O

Primaquine

N

NH

OH

N

Cl

Amodiaquine

Fig. 4 Development of fluoroquinolones from quinacrine. Roughly the same time as mefloquine another important drug; nalidixic acid was invented as naphthyridine byproduct isolated during synthesis of chloroquine. However poor pharmacokinetics restricted its use to urinary tract infections it is considered as trigger of emerging important class of fluoroquinolones [101] and non fluorinated quinolones [102]. This robust group of antibiotics has been under intensive exploitation for 60 years until now which resulted in more than 15 registered drugs [101,103-105]. 6-Fluoro-4-oxoquinoline-3-carboxylic acid moiety is the core of the drugs from this group. Subsequent modification of which resulted in changes in potency, spectrum of activity or pharmacokinetics [106] as comprehensively discussed recently by Andersson and McGowan [103]. Strong position of the fluoroquinolones between antimicrobial therapeutics originates from their broad spectrum of activity and relatively good usability with fewer side effects [107,108]. Pharmacokinetic parameters of these drugs make them suitable for treatment not only urinary tract but systemic or respiratory tract infections [109]. The only weak point of fluoroquinolones is drug resistance emerging as mutation of the two bacterial targets of the drugs: DNA gyrase and topoisomerase IV or as efflux pump overexpression [110]. Nevertheless there are still some news from this potent class of compounds as positive clinical trials for delafloxacin (NCT00719810) [111]. There are reports on further modifications of fluoroquinolone moiety in order to search for even improved activity. Some structures bearing fused aromatic rings have been studied by Al-Trawneh et al [112]. Authors assembled the products on the basis of ciprofloxacin scaffold and ellipticines – alkaloids from Apocynaceae (Dogbane) plants. Ellipticines are known for their cytotoxic activity against various cancer cells. Antibiotics designed this way showed interesting activity covering spectrum of the both substructures. They were superior to ciprofloxacin against several bacteria and to ellipticine against some cancer cells. More recently isatine moiety was used to improve the spectrum activity and potency of ciprofloxacin [113,114].

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N

O

OH

O

NH

R1R2

R3

F

N

O

OH

O

F

R1

N

N

O

R2

R1 = Et, Ar

R2 = F, OMe, H, ClR1-R3 = H, Me, OMe

N

O

OH

O

F

R1

N

R2ON

NH2

R1 = Et, Ar, cyclopropyl

R2 = Me, Et

1 2 3

N

O OH

OF

N

N

O

O 4

Antifungal

Antibacterial

N

NH

Cl

N

Fe 5

Fig. 5 Modification of known antimicrobial drugs. Norfloxacin was also exploited as scaffold for synthesis antibiotics with broad spectrum of activity. Group of derivatives of norfloxacin shown in Fig 5 (2) was synthesized and evaluated against various bacteria and human renal cancer cell lines [115,116]. Gemifloxacin and levoflxacin were used for another study resulting in some derivatives 3 active against resistant bacteria strains MRSA and MRSE [114,117,118]. Antibacterial-antifungal composite (4) was proposed by Yu et al whose introduced moiety of furcarbanil antifungal drug to norfloxacin [119]. Similar study was undertaken on mefloquine and moxifloxacin leading to activity against M.tuberculosis resistant to isoniazyd, rifampicin and etambutol [120,121]. Chloroquine although seriously depreciated by decreasing activity was recently in the spotlight again due to possibility of modification and very good synthetic availability [93]. There are some reports on the structural modification leading to improved activity particularly against resistant pathogens [122-124]. Ferroquine (5) is an interesting example of chloroquine remake by incorporating ferrocene moiety [125,126]. This drug candidate is currently under the clinical trials (as SSR97193), however, there are reports on other research for new structural modifications of chloroquine or similar amodiaquine [127,128]. Chloroquine and endochin were used as scaffolds for derivatisation in search for antimicrobial activity [129]. The small step technique may be an overall impression on recent research on quinoline related antimicrobial drugs in general and fluoroquinolones in particular. Tiny modifications of approved drugs, combining two or more pharmacophores, new use for old drugs – these are all well known approaches in pharmaceutical industry [130]. Apparent drawback of this approach is relatively poor novelty of the developed drugs. On the other hand the research are dramatically less time and cost-consuming.

4. Conclusions

Unambiguously our struggling with pathogenic microbes may resemble a war. War with no battle to give us the victory. New drugs have, no doubt impressive activity and desired pharmacokinetic parameters. They are much safer and efficient against various microbes than any before. On the other hand microbes have the evolutionary feature – resistance. The more keen we are in use even abuse our drugs the sooner the resistance come to the existence. Growing of our arsenal of drugs do not altered the efficiency of treatment. Millions of dollars spent on research and development of particular new braking-through drugs may be almost instantly wasted by resistance, mutations, incidental side effects and high costs of therapy – especially in developing countries. Paradoxically the oldest drugs are still in use in many places mostly endangered by neglected diseases – whose are mainly of microbial origin. Over the passage of time new trend may be identified. Natural drugs are again interesting but as inspiration rather than pure ointment or decoction. Setting our eyes again on quinine and similar alkaloids as well as on most robusted

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group of antimicrobial drugs quinolones we understood the importance of strong background. In terms of drug design such background is molecular scaffold flexible for development and strong enough for good activity. The historical insight into the research on antimicrobial drugs reveals that quinoline may be suitable as such scaffold.

Acknowledgements The support by the Polish Ministry of Science and Higher Education grant no N N519 575638 is greatly appreciated.

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