Quinolone Antibacterials Research Articles

Conductometric Determination of the Stability Constants of the Quinolone Antibacterial Agents Levofloxacin and Sparfloxacin with Divalent Metal Ions

The stability of the metal ion complexes of the fluoroquinolone antibiotics sparfloxacin and levofloxacin with the divalent magnesium, calcium, barium and nickel perchlorates has been investigated by electrical conductivity in methanol at 25 o C. Under the experimental conditions used, it was found that the metal ions interact with ligands in the zwitterionic state leading to the formation of positively charged complexes. The complexes of levofloxacin with the four metal ions are slightly more stable than those of sparfloxacin due to the differences in the substitution pattern between the two ligands. The stability of the complexes formed decreases in the order Mg 2+ > Ca 2+ > Ni 2+ > Ba 2+ . The observed order of decrease of the complex stability is attributed to the variation in ionic radii between metal ions and to the nature of the interaction between the ligands and the metal ions.

First- and second-generation quinolone antibacterial drugs interacting with zinc(II): Structure and biological perspectives

Interaction of equimolar quantities of ZnCl2 with the quinolone antibacterial drugs flumequine (Hflmq), oxolinic acid (Hoxo) or enrofloxacin (Herx) and the N,N′-donor heterocyclic ligands 1,10-phenanthroline (phen) or 2,2′-bipyridine (bipy) results in the formation of 1:1 drug to metal complexes with the general formula [Zn(quinolone)(N,N′-donor)Cl], while excess of the quinolone leads to 1:2 metal to drug [Zn(quinolone)2(N,N′-donor)] complexes. In all complexes, the deprotonated bidentate quinolonato ligands are coordinated to zinc ion through the pyridone oxygen and a carboxylato oxygen. The crystal structures of [Zn(oxo)(phen)Cl], [Zn(flmq)(phen)Cl] and [Zn(flmq)2(phen)] have been determined by X-ray crystallography. All complexes exhibit good binding propensity to human or bovine serum albumin protein showing relatively high binding constant values. Interaction of the complexes with calf-thymus (CT) DNA, studied by UV spectroscopy, has shown that they bind to CT DNA, while [Zn(flmq)(phen)Cl] and [Zn(flmq)2(phen)] complexes exhibit the highest binding constants to CT DNA. Competitive study with ethidium bromide (EB) has shown that all complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. Intercalative binding mode is proposed for the interaction of the complexes with CT DNA and has also been verified by DNA solution viscosity measurements. DNA electrophoretic mobility experiments suggest that all complexes bind to linearized pDNA and supercoiled pDNA by intercalative manner resulting in catenanes formation as well as in double-stranded cleavage reflecting (or ending) in the formation of linear DNA. The complexes exhibit significant antimicrobial activity tested on five different microorganisms.

In Silico Assessment of Adverse Effects of a Large Set of 6-Fluoroquinolones Obtained from a Study of Tuberculosis Chemotherapy

Among the different chemotherapeutic classes available today, the 6-fluoroquinolone (6-FQ) antibacterials are still one of the most effective cures in fighting tuberculosis (TB). Nowadays, the development of novel 6-FQs for treatment of TB mainly depends on understanding how the structural modifications of the main quinolone scaffold at specific positions affect the anti-mycobacterial activity. Alongside the structure-activity relationship (SAR) studies of the 6-FQ antibacterials, which can be considered as a golden rule in the development of novel active antitubercular 6-FQs, the structure side effects relationship (SSER) of these drugs must be also taken into account. In the present study we focus on a proficient implementation of the existing knowledge-based expert systems for design of novel 6-FQ antibacterials with possible enhanced biological activity against Mycobaterium tuberculosis as well as lower toxicity. Following the SAR in silico studies of the quinolone antibacterials against M. tuberculosis performed in our laboratory, a large set of 6-FQs was selected. Several new 6-FQ derivatives were proposed as drug candidates for further research and development. The 6- FQs identified as potentially effective against M. tuberculosis were subjected to an additional SSER study for prediction of their toxicological profile. The assessment of structurally-driven adverse effects which might hamper the potential of new drug candidates is mandatory for an effective drug design. We applied publicly available knowledge-based (expert) systems and Quantitative Structure-Activity Relationship (QSAR) models in order to prepare a priority list of active compounds. A preferred order of drug candidates was obtained, so that the less harmful candidates were identified for further testing. TOXTREE expert system as well as some QSAR models developed in the framework of EC funded project CAESAR were used to assess toxicity. CAESAR models were developed according to the OECD principles for the validation of QSAR and they turn to be appropriate tools for in silico tests regarding five different toxicity endpoints. Those endpoints with high relevance for REACH are: bioconcentration factor, skin sensitization, carcinogenicity, mutagenicity, and developmental toxicity. We used the above-mentioned freely available models to select a set of less harmful active 6-FQs as candidates for clinical studies.

Topoisomerase Inhibition, Nucleolytic and Electrolytic Contribution on DNA Binding Activity Exerted by Biological Active Analogue of Coordination Compounds

The neutral mononuclear copper complexes with the quinolone antibacterial drug ciprofloxacin and bipyridine derivatives have been synthesized and characterized. Complexes were screened for their antibacterial activity against three Gram((-)) and two Gram((+)) bacteria, and study suggests inhibition of gyrase activity by metal complexes as the possible mechanism. The nucleolytic activity of adducts was carried out on double stranded pUC19 DNA using gel electrophoresis in the presence of radical scavenging agents that suggest hydrolytic cleavage mechanism for plasmid DNA.

Heterocyclic urea derivatives and methods of use thereof (WO2010142978)

A series of ureido derivatives incorporating a highly derivatized quinolone scaffold were prepared by a succession of original steps. The lead molecules of these compounds are the quinolone antibacterials of the nalidixic acid/ciprofloxacin type and they target, similar to these clinically used agents, the DNA gyrase/topoisomerase IV of pathogenic bacteria. These new quinolones are claimed to act as efficient antibacterials against a large number of drug-resistant bacteria such as Staphylococcus spp., Enterococcus spp., Streptococcus spp., Acinetobacter baumannii, Bacteroides bivius, Burkholderia spp., Chlamydia spp., Chlamydophila pneumoniae.

Nickel complexes of the different quinolone antibacterial drugs: Synthesis, structure and interaction with DNA

Three new nickel (II) complexes of the second/third-generation quinolone antibacterial drugs have been synthesized and structurally characterized. Single-crystal X-ray diffraction analysis shows that complex 1 exhibits 1D chain structure, and 2 and 3 2D sheet structures. UV study of the interaction of the complexes with calf-thymus DNA (CT-DNA) shows that complexes 1–3 can bind to the CT-DNA and exhibit the higher binding constant to CT-DNA than their parent drugs. Additionally, their competitive study with ethidium bromide (EB) also indicates that complexes can bind to DNA for the intercalative binding sites except for 1. Note that, due to uncoil the helix structure of DNA, 1 presents a higher value for KSV and Kb than other complexes.

The introduction of antibacterial drug pipemidic acid into the POM field: Syntheses, characterization and antitumor activity

Two new compounds based on polyoxometalates (POMs) and the quinolone antibacterial drug pipemidic acid (HPPA), {[Ni(PPA) 2]H 4[SiW 12O 40]}·HPPA·3H 2O ( 1), and {[Zn(PPA) 2] 2H 4[SiW 12O 40]}·3H 2O ( 2), have been synthesized under hydrothermal conditions and structurally characterized by routine technique. Single-crystal X-Ray diffraction analysis shows that compound 1 is constructed by Keggin clusters grafted by binuclear nickel clusters, isolated HPPA and water molecules, while compound 2 consists of Keggin clusters grafted by binuclear zinc clusters and water molecules. Due to the selection of different transition metal (TM) ions, compounds 1 and 2 exhibit different structures and antitumor activities. Compound 1 possesses 0D structure and shows no antitumor activities. However, compound 2 possesses 1D structure and exhibits higher antitumor activities than its parent compound. The results show that introduction of different TM-PPA moieties onto the polyoxoanion surface can affect not only the final structures but also their antitumor activities.

Physicochemical Studies and Anticancer Potency of Ruthenium η6-p-Cymene Complexes Containing Antibacterial Quinolones

With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochemical properties were compared to those of chlorido(η6-p-cymene)(ofloxacinato-κ2O,O)ruthenium(II) (1). All compounds undergo a rapid ligand exchange reaction from chlorido to aqua species. 2 and 3 are significantly more stable than 1 and undergo minor conversion to an unreactive [(cym)Ru(μ-OH)3Ru(cym)]+ species (cym = η6-p-cymene). In the presence of human serum albumin 1−3 form adducts with this transport protein within 20 min of incubation. With guanosine 5′-monophosphate (5′-GMP; as a simple model for reactions with DNA) very rapid reactions yielding adducts via its N7 atom were observed, illustrating that DNA is a possible target for this compound class. A moderate capacity of inhibiting tumor cell proliferation in vitro was observed for 1 in CH1 ovarian cancer cells, whereas 2 and 3 turned out to be inactive.

Interaction of Zn(ii) with quinolone drugs: Structure and biological evaluation

Zinc complexes with the third-generation quinolone antibacterial drugs levofloxacin and sparfloxacin have been synthesized and characterized. The deprotonated quinolones act as bidentate ligands coordinated to zinc ion through the pyridone and a carboxylato oxygen atom. The crystal structures of [bis(aqua)bis(levofloxacinato)zinc(II)], 1, and [bis(sparfloxacinato)(1,10-phenanthroline)zinc(II)], 3, have been determined by X-ray crystallography. The biological activity of the complexes has been evaluated by examining their ability to bind to calf-thymus DNA (CT DNA) by UV spectroscopy and viscosity measurements. UV studies of the interaction of the complexes with DNA have revealed that they can bind to CT DNA probably by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. The DNA binding constants have been also calculated. A competitive study with ethidium bromide (EB) showed that the complexes exhibit the ability to displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB for the intercalative binding site. The interaction of the complexes with human and bovine serum albumin proteins has been studied by fluorescence spectroscopy showing that the complexes exhibit good binding propensity to these proteins having relatively high binding constant values. The biological properties of the complexes have been evaluated in comparison to the previously reported Zn(II) complexes with the first- and second-generation quinolones oxolinic acid and enrofloxacin.

Antibacterial, DNA interaction and superoxide dismutase activity of drug based copper(II) coordination compounds

The novel neutral mononuclear copper(II) complexes with the quinolone antibacterial drugs ciprofloxacin in the presence of the nitrogen donor heterocyclic ligand of terpyridine have been synthesized and characterized by elemental analysis, reflectance spectra, IR and mass spectroscopy. The antibacterial activities of the newly synthesized compounds were evaluated and correlated with their physicochemical properties. Results revealed that the tested compounds exhibited better inhibitory activities than the reference antibacterial quinolone drugs against Gram (+ve) and Gram (−ve) bacteria. The coordination compounds can act as catalysts for the dismutation of superoxide anion radicals ( O 2 · - ). The detection of the rate constant of the reaction of superoxide ion with nitro blue tetrazolium (NBT) is inhibited by superoxide dismutase (SOD). The interaction of the complex with DNA was investigated using viscosity, absorption titration and DNA melting temperature techniques. The results indicate that the complexes bind to DNA with intercalative mode and they have rather high DNA-binding constants. DNA-cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drugs.

Metal complexes of the third generation quinolone antibacterial drug sparfloxacin: preparation, structure, and microbial evaluation

The interactions of yttrium chloride, zirconium chloride, and uranium nitrate with sparfloxacin (SPAR) in ethanol, methanol, and acetone were studied. The isolated solid complexes were characterized by elemental analysis, infrared, 1H-NMR and electronic spectra, and thermogravimetric analysis. The results support the formation of [Y(SPAR)2Cl2]Cl ⋅ 12H2O, [ZrO(SPAR)2Cl]Cl ⋅ 15H2O, and [UO2(SPAR)3](NO3)2 ⋅ 5H2O. Infrared spectra of the isolated solid complexes indicate that SPAR is bidentate through the ring carbonyl oxygen and one oxygen of carboxylate. The calculated bond length and force constant, F(U=O), in the uranyl complex are 1.747 Å and 655.29 Nm−1, respectively. The antimicrobial activities of the ligand and metal complexes have been tested against bacteria Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) and fungi Penicillium rotatum (P. rotatum) and Trichoderma sp., showing that the complexes exhibit higher antibacterial activity than SPAR.

Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance

Quinolone antibacterials have been used to treat bacterial infections for over 40 years. A crystal structure of moxifloxacin in complex with Acinetobacter baumannii topoisomerase IV now shows the wedge-shaped quinolone stacking between base pairs at the DNA cleavage site and binding conserved residues in the DNA cleavage domain through chelation of a noncatalytic magnesium ion. This provides a molecular basis for the quinolone inhibition mechanism, resistance mutations and invariant quinolone antibacterial structural features.

ChemInform Abstract: Quinolone Antibacterial Agents Substituted at the 7-Position with Spiroamines. Synthesis and Structure-Activity Relationships.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Quinolone Antibacterials: Preparation and Activity of Bridged Bicyclic Analogues of the C7-Piperazine.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis and Antibacterial Activity of New Tetracyclic Quinolone Antibacterials.

A series of 8-substituted-9,1-(epoxymethano)-7-fluoro-5-oxo-5H- thiazolo[3,2-a]quinoline-4-carboxylic acids having a novel tetracyclic structure was synthesized and tested for antibacterial activity. The nature of the heteroatom (N, O, or S) substituted at the 8-position had little influence on the antibacterial activity. Among the six pyrrolidinyl derivatives and the five piperazinyl derivatives, the 8-(3-hydroxy-1-pyrrolidinyl) derivative 6h and the hydrochloride of the 8-(4-methyl-1-piperazinyl) derivative 6l showed the most potent activity against both Gram-positive and Gram-negative bacteria. Against nalidixic acid resistant strains, isolated from Escherichia coli KC-14, compound 6h was less potent than 6l. Replacement of the piperazinyl nitrogen atom by a carbon atom, an oxygen atom, or a sulfur atom (corresponding to the piperidino, morpholino, or thiomorpholino group, respectively) enhanced the activity against Gram-positive bacteria, but reduced the activity against Gram-negative bacteria. Compound 6l also showed potent in vivo antibacterial activity against Gram-positive and Gram-negative bacteria, and did not cause convulsions in mice with the concomitant administration of fenbufen. Replacement of the carboxy group by a sulfonic acid group in 6l resulted in a complete loss of antibacterial activity.

ChemInform Abstract: Synthesis of a New Bridged Diamine: 3,6-Diazabicyclo(3.2.0)heptane. Applications to the Synthesis of Quinolone Antibacterials.

Abstract Diprotected 3,6-diazabicyclo [3.2.0] heptane has been prepared by an highly efficient process. Selective deprotection, followed by condensation with 7-halogenoquinolones led to the naphthyridones 10 and 13 and the quinolone 14 .

ChemInform Abstract: Synthesis of 4H-1,4-Benzothiazine 1-Oxide and 1,1-Dioxide. Analogs of Quinolone Antibacterial Agents.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Dual-Action Cephalosporins: Cephalosporin 3′-Quinolone Carbamates.

A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibacterial spectrum derived from both cephalosporin-like and quinolone-like activities, suggesting a dual mode of action. Studies to elucidate details of the mechanism of action have been inconclusive. Ciprofloxacin liberated as a consequence of bacterial enzyme-mediated reactions may contribute to the second mode of action, although some evidence indicates that the intact carbamate-linked bifunctional molecules may possess intrinsically both beta-lactam and quinolone activities.

ChemInform Abstract: Synthesis of (1R,4S,5R)-endo-N,N-Dimethyl-2-azabicyclo(2.2.1) methanamine.

Starting from trans-4-hydroxy-L-proline, (1R,4S,5R)-endo-N,N-dimethyl-2-azabicyclo[2.2.1]methanamine 1 has been synthesized. The target compound is precursor of antibacterial quinolone carboxylic acids.

ChemInform Abstract: The Synthesis and Biological Activity of New 7-(2-(Cyanomethyl) piperazinyl)- and 7-(3-(Cyanomethyl)piperazinyl)quinolone Antibacterials.

Some novel 7-[2- or 3-(cyanomethyl)piperazinyl]quinolones have been prepared. Most notable, 2-cyano-methyl-piperazine 5 and 1 -methyl-2-cyanomethylpiperazine 8 at the quinolone C-7 position produce products with good in vitro antibacterial activity. The key step in the synthesis of these products involves the regioselective deprotection of the benzyl group in function of the time reaction