Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules
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This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis-quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents.
KeywordsAntibiotics Antitumor agents Antiviral activity Conjugates Drug research Hybrid drugs
In recent years, the concept of “dual-action drugs” has been gaining popularity in medicinal chemistry and medicine. Since a single drug is not always able to adequately control the illness, the combination of drugs with different pharmacotherapeutic profile may be needed . Drugs involving the incorporation of two biologically active compounds in a single molecule with the intention of exerting dual drug action have been described . For example, one of the hybrid parts may be incorporated to counterbalance the known side effects associated with the other hybrid part, or to amplify its effects through action on another biological target. In addition, hybrid drugs could be used to avoid fast developing bacterial resistance caused by frequent mutations in bacterial genome.
Interestingly, the fluoroquinolone chemotherapies linked to another antibacterial agent represent the most comprehensively described hybrid compounds. This review deals with the recent literature (2007–2017) concerning custom applications of quinolones and fluoroquinolones, as well as their hybrid conjugates with dual or enhanced action mechanisms.
Copper is one of the most important biometals due to its biological role and potential synergetic activity with drugs . Cu(II) complexes with drugs are much more active in the presence of nitrogen-donor heterocyclic ligands, such as 2,2′-bipyridine, 1,10-phenanthroline, or 2,2′-dipyridylamine . Hernández-Gil and coworkers reported the synthesis of two new ternary complexes of Cu(II) with ciprofloxacin and 1,10-phenanthroline. The aim of the study was to obtain artificial nucleases capable of cleaving DNA chains. The nucleolytic activity of copper complexes with nitrogen-donor heterocyclic ligand was revealed in the presence of H2O2 and reducing agents . The chemical nuclease activity tests were performed in the presence of ascorbate and have shown that both complexes are efficient in DNA breaking. Mechanistic studies with various radical oxygen scavengers were undertaken and revealed that the cleavage reaction is mediated by hydroxyl radicals, superoxide anion, and singlet oxygen .
Complexes of copper(I) iodide or copper(I) thiocyanate and phosphine derivative of sparfloxacin bearing auxiliary steric hindered diimine ligands (2,9-dimethyl-1,10-phenanthroline or 2,2′-biquinoline (2)) were prepared by Komarnicka and coworkers. Phosphine ligand was used to avoid oxidation and hydrolysis reactions by a strong copper–phosphine interaction. The conjugates obtained were tested against CT26 (mouse colon carcinoma) and A549 (human lung adenocarcinoma) cancer cell lines. The cytotoxicity of all compounds was found to be significantly increased (IC50 6.04 ± 0.3–42.64 ± 0.73) in comparison with free sparfloxacin (IC50 122.84 ± 4.21–273.50 ± 10.63) and extremely higher than cisplatin (IC50 222.45 ± 10.78–298.12 ± 13.09) .
Neutral sparfloxacin–copper complexes were also utilized by Efthimiadou and coworkers. They prepared conjugates bearing ligands such as 2,2′-bipyridine (3), 1,10-phenanthroline, or 2,2′-dipyridylamine in high yields (65–70%) by the template reaction of equimolar quantities of the deprotonated sparfloxacin, CuCl2, and the corresponding N-donor ligand. The copper atom in obtained conjugates was five-coordinative and had slightly distorted square pyramidal geometry. Sparfloxacin was bound to Cu(II) via the pyridone and one carboxylate oxygens. The interactions of complexes with calf-thymus DNA showed that the complexes are able to bind DNA by intercalation mode. Antibacterial activity was tested against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The conjugates were found to be more active than the parent drug against E. coli, but less active against remaining strains of bacteria with the lowest MIC values obtained for complexes bearing 2,2′-bipyridine and 1,10-phenanthroline ligands. These two complexes were tested as potential anticancer agents against human leukemia cell line HL-60 (peripheral blood human promyelocytic leukemia) in MTT assays and showed enhanced cytotoxic properties compared to free sparfloxacin which displayed no cytotoxic effect .
Shingnapurkar and coworkers also prepared sparfloxacin–Cu complexes having butterfly motif to expand fluoroquinolone activity on anti-proliferative properties against cancer cells. Fluoroquinolones are able to inhibit DNA topoisomerase in mammalian cells. This enzyme is overexpressed in hormone independent breast cancer cell lines. The complexes of fluoroquinolone and copper alone or with appended ancillary ligands, namely, 2,2′bipyridine, 1,10-phenanthroline (4), and 4,5-diazafluoren-9-one, were synthesized and characterized. The obtained conjugates were tested against BT20 breast cancer cell line IIα. IC50 values of novel complexes were four- to tenfold lower than in case of the parent drug indicating that anti-proliferative activity of quinolones may be related to their metal chelating ability. The dimeric compound of sparfloxacin and copper without additional ligands was the most potent molecule in the series .
Another research group synthesized moxifloxacin–copper complexes showing antitumor activity against breast cancer cells. They prepared four new conjugates, with or without additional ligands (pyridyl, bipyridyl (5), and phenanthroline), and performed anti-proliferative tests against estrogen-independent MDA-MB-231 and BT-20, as well as hormone-dependent MCF-7 and T47D cancer cell lines. All the conjugates were able to induce activity of caspases-3/7 and apoptosis in breast cancer cells with no toxic effect on MCF-10A, normal breast epithelial cell line. Moxifloxacin alone did not exhibit any anti-proliferative or apoptosis-inducing properties against any of the cell lines examined; however, when complexed with copper, it exhibited divergent cancer cell-specific activity with the strongest effect for phenanthroline adduct .
Complexes of copper and moxifloxacin or gatifloxacin bearing bipyridyl or phenanthroline ligands were also prepared by Singh and coworkers and tested in human lung carcinoma cells A-549. The highest cytotoxic activity exhibited complex 6 [gatifloxacin–Cu(II)-bipyridyl]. DNA fragmentation, cell shrinkage, transformation of cells into small membrane-bound vesicles or apoptotic bodies were observed in treated cells. Late apoptosis was perhaps induced by chromatin condensation. The metal complexes enhanced the apoptotic effect of the parent quinolone drugs, which may be useful for designing more effective drugs against lung cancer .
Nanoparticles and nanodrugs
Biopolymer encapsulation of drug to form micro- and nanoparticles can be used as a drug delivery tool to change bioavailability, modify pharmacokinetics, target the drug, and redirect the antibiotic to tissues or organs, where infection occurs. Fluoroquinolones exhibit high affinity for binding Mg2+, which causes a depletion of the ion in bones and articular cartilage. The concentration of ofloxacin (fluoroquinolone widely used in hospitals) in the articular cartilage is three times higher than the corresponding concentration in plasma . Lee and coworkers formed microparticles of albumin and hypromellose acetate succinate (HPMCAS) containing ofloxacin achieved by the spray dry method. Albumin was chosen, because it is biocompatible, biodegradable, and non-toxic natural protein component of blood . HPMCAS is a hydrophilic cellulose derivative bearing succinyl groups and acts as entering coating agent. The obtained particles’ morphology was spherical with a smooth surface. Particle size (0.1–7 µm) depended on ofloxacin concentration. Ofloxacin nanospheres were administrated to BALB/c mice and good distribution was maintained. The release of ofloxacin was more sustained than ofloxacin in solution in all organs tested (spleen, brain, liver, and lung). This particle formulation is more favorable for treatment of diseases that affect the liver and brain, because the release from the particles was extended there by 24 and 48 h, respectively, and dosing regimens would be improved by less frequent dosing .
A different approach was used by Marslin and coworkers . They used nanoparticles made of two different polymers, namely, poly(d,l-lactic-co-glycolic acid (PLGA) and methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG–PLGA), to improve the efficiency of ofloxacin delivery at the site of action and inhibition of its extrusion. Since polyethylene glycol (PEG) is commonly used for drug conjugation and has the ability to bind DNA  and block drug efflux pump , the hypothesis was that mPEG–PLGA will improve antibacterial activity. The copolymer methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG–PLGA) was prepared by ring-opening polymerization of PLGA and mPEG in the presence of stannous octanoate as a catalyst. Ofloxacin encapsulated mPEG–PLGA and PLGA nanoparticles wa prepared by the emulsion solvent evaporation method. The nanoparticles exhibited a smooth spherical shape and were heterogeneous in their size; no aggregation or adhesion was observed. The obtained nanoparticles were tested on clinically important human pathogenic strains (E. coli, P. aeruginosa, Proteus vulgaris, Salmonella typhimurium, Klebsiella pneumoniae, and S. aureus) and markedly improved bacterial uptake and bacteriocidal activity compared to free ofloxacin. The ofloxacin–mPEG–PLGA nanoparticles displayed higher antibacterial activity, efficient bacterial uptake, sustained release, and strict control of bacterial growth. PEGylation increased bacterial membrane permeability, allowing the accumulation of mPEG–PLGA nanoparticles inside the cells to a greater extent than PLGA nanoparticles. The nanoformulation also delayed the development of bacterial resistance in comparison with the free drug .
Polymer antibiotic conjugates afford lower toxicity, increased solubility, and prolonged activity of the drug, which have extensive applications in many fields, such as food packing or medical items . They show remarkable high activity against the resilient biofilms . Localized delivery methods based on physical stabilization of antibiotics in a polymer matrix such as a hydrogel or self-eluting polymer can release chemotherapeutics at the target region to maintain a high local concentration without exceeding systemic toxicity limits .
Proteins and peptides
Kumar and coworkers synthesized enrofloxacin conjugated with bovine serum albumin (BSA) to use the conjugate as an antigen capable of producing polyclonal antibodies against the antibiotic. Enrofloxacin belongs to antibacterials commonly used in veterinary practice in the treatment of infectious diseases as well as prophylactic agent; therefore, the produced antibodies could be employed for the detection of antibiotics in milk samples. To obtain immunogens, the carbodiimide reaction was employed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) as a crosslinker. Polyclonal antibodies were successfully produced in rats, which were confirmed by indirect ELISA .
German and coworkers prepared conjugates of ciprofloxacin and ofloxacin with dipeptides or bisarylurea to expand action of the antibiotics on the substrate-based inhibitors of bacterial efflux pumps. Fluoroquinolone resistance in S. aureus may be caused by the norA-encoded and mepA-encoded fluoroquinolone efflux pump systems ; therefore, coadministration of bacterial efflux pump inhibitors with antibiotic agents led to overcome the efflux-mediated resistance . Bisaryl urea and dipeptide components, known inhibitors of NorA and MexAB pumps, respectively, were selected for incorporation to the C7 position of fluoroquinolone core. The conjugation of urea was achieved by attachment of bisaryl urea to the C7 piperazine of ciprofloxacin or C7 amine of ofloxacin precursor in direct alkylation (12a, 12b) (Scheme 8). Ciprofloxacin conjugates bearing Phe–Lys or Lys–Phe moiety was obtained with use of standard amino-acid coupling chemistry to modify the C7 piperazine moiety (13a, 13b) (Scheme 8). The novel compounds were tested against E. coli, P. aeruginosa, and S. aureus strains. In all cases, activities of conjugates were significantly lower than the parent drugs. None of the conjugates achieved appreciable inhibition of efflux pump system at any tested concentration in P. aeruginosa efflux inhibition studies. However, ofloxacin–urea conjugate 12b exhibited the highest inhibitor potencies of NorA and MepA efflux pump systems in S. aureus efflux inhibition assays and at 0.5 µM concentration inhibited NorA-mediated and MepA-mediated efflux by 73.6 and 53.4%, respectively .
NO donors and analogs
Nitric oxide (NO) is an inorganic free radical gaseous molecule important in a variety biofilm-forming species for signaling. Used at low, sub-lethal concentrations, NO is capable to induce a transition from the sessile biofilm state to a dispersed (planktonic) mode of growth . Due to a short half-life of NO (0.1–5 s) and its extreme chemical reactivity, NO-donor molecules are used to deliver the drug into systems, where biofilms are prevalent .
Nitroxides are also useful crystalline solids structurally similar to NO. They undergo redox chemistry and exhibit antibacterial effect. Ciprofloxacin–nitroxide hybrids 23b, 24b, 23d, 24d, and 24f were synthesized and evaluated as anti-biofilm agents (Scheme 12). The methoxyamine derivatives 23a, 24a, 23c, 24c, and 24e were prepared as a control to enable direct comparison (Scheme 12). Compounds 23a–23d were obtained via a tertiary amine linker by reductive amination followed by deprotection of ethyl ciprofloxacin esters, while compounds 24a–24f were synthesized using amide bond coupling with corresponding acyl chloride. The desired products were obtained in good-to-excellent yields (64–98%) and antibacterial activity was measured against biofilm-forming P. aeruginosa strain. The results indicate that the nitroxide hybrids possess dual-action effect. The most active hybrid 23b showed dispersal activity towards mature biofilm and antibiotic action by means of eradication of the newly dispersed bacteria up to 95% at 40 µM . Compounds 24b, 24d, and 24f also displayed good anti-biofilm activity. Compound 24d removed 85% of existing biofilms at 20 µM (10.95 µg/cm3). Free ciprofloxacin was ineffective at biofilm removal; however, the addition of nitroxide moiety to the piperazine ring through amide bonds, in general, has resulted in decreased activity against planktonic forms of bacteria. Selected compounds examined in human muscle rhabdomyosarcoma and human embryonic kidney 293 (HEK-293) cells were found to be non-toxic up to the highest concentrations used (40 µM) .
Certain pathogenic microorganisms under iron-limited conditions synthesize and excrete low-molecular-weight molecules called siderophores, able to chelate low-bioavailable Fe(III) from the surrounding environment and compete with the host for this element . Siderophore–Fe(III) complex is recognized by the dedicated membrane receptors and transported into the bacterial cell. Then iron is released from the complex for further use, which allows the bacteria to survive in iron-deficient media. Sideromycins are natural conjugates of an antibiotic molecule and a siderophore analog, often connected by a hydrolyzable linker that can be cleaved by endogenous enzymes. These components are recognized and transported into the targeted bacteria by the siderophore-dependent iron uptake pathways. After the sideromycin has been transferred across the bacterial envelope, the antibiotic is released . This natural strategy can be used in Trojan horse approaches using synthetic siderophores as vectors to transport antibiotics into the bacterial cells .
Prodrugs with enhanced lipophilicity
Dhaneshwar and coworkers employed ester prodrug strategy to improve oral bioavailability of norfloxacin, fluoroquinolone which enter into cells by diffusion . Because of low lipophilicity, diffusion process is very low and the drug is unable to attain therapeutic concentration at the site of infection. Dhaneshwar research group used diglyceride promoiety to enhance bioavailability of poorly absorbed norfloxacin. They synthesized norfloxacin 1,3-dipalmitin ester via coupling of 2-hydroxypropane-1,3-diyl dipalmitate with BOC-protected piperazinyl ring of norfloxacin, followed by deprotection with the TMSBr (Scheme 21). Thus, lipases mediated hydrolysis of the diglyceride ester linkage would release the parent drug norfloxacin in the tissue. The partition coefficient of the novel prodrug 36 determined in chloroform/phosphate buffer reached 5.25 and was 2.7 times higher compared to the parent drug. The release kinetics was examined in vivo in blood, faeces, and urine in Wistar rats’ model. The studies indicated improved pharmacological profile .
Quinolones represent an extremely interesting class of synthetic bactericides that can be exploited as precursors and building blocks for the synthesis of a wide range of organic molecules and coordination complexes, active pharmaceutical ingredients, and polymers. The huge number of publications which continuously describe novel methods to synthesize and to derivatize quinolones substrates account for their versatility and use in many fields of medicinal chemistry. Most of the methods for the synthesis of quinolone conjugates rely on the catalyzed and uncatalyzed coupling reactions. There are many promising directions in the application of novel quinolone conjugates in fields such as polymer engineering, biomaterials development and the design of novel hybrid bifunctional drugs. It is certain that quinolone modifications will continue to attract the attention of many research groups and that improvements in their biological potency as well as novel transformations of these compounds will be reported in the literature in the near future.
We are grateful to the National Science Centre, Poland, for financial support (Research Grant 2016/21/N/NZ7/03464).
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