Preparation and evaluation of three mucoadhesive dosage forms using (99m)Tc-Ofloxacin.

Preparation of three mucoadhesive formulations was optimized and pharmaceutically evaluated. Ofloxacin was radiolabeled with (99m)Tc and radiolabeled complex was characterized by HPLC. (99m)Tc-Ofloxacin was added as a tracer to the formulations namely Oflox C934, Oflox C940 and Oflox HPMC and the formulations were fed orally to rats. Imaging studies were carried out to assess the prolonged gastric retention of the formulations. (99m)Tc-Ofloxacin served as a good tracer for studying the pharmacokinetics of three controlled release mucoadhesive dosage forms by gamma scintigraphy studies.

(99m) Tc-tricabonyl labeling of ofloxacin and its biological evaluation in Staphylococcus aureus as an infection imaging agent.

Even in recent decades, one of the major causes of death and unhealthiness in the whole world is infection and inflammation. The use of radiopharmaceuticals is a powerful tool in managing the patients with infectious diseases. In this study, ofloxacin as a second-generation fluoroquinolone has been labeled with [(99m) Tc(CO)3 (H2 O)3 ](+) core to formulate a suitable infection imaging agent. Ofloxacin was radiolabeled with (99m) Tc using carbonyl core. Radioligand chemical analysis involved HPLC methods. Radioconjugate stability and lipophilicity were determined. Binding with Staphylococcus aureus and biodistribution in infected mice for labeled compound were studied. The radioligand was characterized by HPLC, and its radiochemical purity was more than 90%. In vitro stability studies have shown the complex was stable at least 6 h after labeling at room temperature. The n-octanol/water partition coefficient experiment exhibited logP = 1.52 ± 0.21 for (99m) Tc(CO)3 -ofloxacin. The complex showed specific binding to S. aureus. Biodistribution results showed that radioligand had high accumulation in the infected muscle in a mice (T/NT = 2.02 ± 0.12 at 4 h postinjection). On the basis of stability and infection site uptake ratio, suitability of this complex as a radiotracer for imaging of infections is recognized.

Synthesis, characterization and antibacterial studies of a copper(II) levofloxacin ternary complex.

Solution behavior of levofloxacin (lvx) complexes with copper(II) in the presence and absence of phen was studied in aqueous solution, by potentiometry. The results obtained show that under physiological conditions (micromolar concentration range and pH 7.4) only copper(II):lvx:phen ternary complexes are stable. Hence, a novel copper(II) ternary complex of fluoroquinolone levofloxacin with nitrogen donor heterocyclic ligand phen was synthesized and characterized by means of UV-Visible and IR spectroscopy, elemental analysis and X-Ray crystallography. In the synthesized complex (1), [Cu(lvx)(phen)(H(2)O)](NO(3)).2H(2)O, levofloxacin acts as a bidentate ligand coordinating to the metal, in its anionic form, through the carbonyl and carboxyl oxygens and phen coordinates through two N-atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth ligand of the penta-coordinated Cu(II) centre is occupied axially by an oxygen atom from a water molecule. Minimum inhibitory concentration (MIC) determinations of the complex and comparison with free levofloxacin in various E. coli strains indicated that the Cu-complex is as efficient an antimicrobial as the free antibiotic (both in the case of the dissolved synthesized complex and the complex formed following stoichiometric mixture of the individual components in solution). Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complex's suitability as a candidate for further biological testing in fluoroquinolone-resistant microorganisms.

N-heterocycle construction via cyclic sulfamidates. Applications in synthesis.

When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (-)-aphanorphine, (+)-laccarin and (-)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.

Recognition mechanism of water-compatible molecularly imprinted solid-phase extraction and determination of nine quinolones in urine by high performance liquid chromatography.

Novel water-compatible molecularly imprinted polymers (MIPs) were synthesized in methanol-water systems with ofloxacin as templates and methacryclic acid as functional monomers. The MIPs were used as a special sorbent for the selective solid-phase extraction (SPE) of nine quinolones from urine samples, showing high affinity to the quinolones in aqueous environment. Its molecular recognition mechanisms were investigated by the molecular simulation and the experimental validation with UV and infrared spectrogram as well as (1)H NMR. Binding capability and chromatographic characteristic were also evaluated. By using the water-compatible MIPs as SPE sorbents, the nine quinolones can be selectively extracted and enriched, while all matrices interferences were eliminated simultaneously. Under the optimal conditions of SPE and high performance liquid chromatography (HPLC), the good linearity of the method was obtained in a range of 0.05-30microg/mL with the correlation coefficient of >0.999 and the relative standard division of 2.0-7.4%. The detection limits (s/n=3) were in a range of 0.036-0.10microg/mL. The proposed method was successfully applied for the selective extraction and separation of the studied quinolones in urine samples.

Enantiopure 1,4-benzoxazines via 1,2-cyclic sulfamidates. Synthesis of levofloxacin.

1,2-Cyclic sulfamidates undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols (and related anilines and thiophenols), followed by Pd(0)-mediated amination to provide an entry to substituted and enantiomerically pure 1,4-benzoxazines (and quinoxalines and 1,4-benzothiazines). This chemistry provides a short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 19, a late stage intermediate in the synthesis of levofloxacin.

Solution studies on binary and ternary complexes of copper(II) with some fluoroquinolones and 1,10-phenanthroline: Antimicrobial activity of ternary metalloantibiotics.

Interaction of norfloxacin and ofloxacin with copper(II) and copper(II)/phenanthroline has been studied in aqueous solution and the stability constants of the binary complexes Cu(II)/fluoroquinolone and of the ternary complexes Cu(II)/phenanthroline/fluoroquinolone have been determined by potentiometry and UV-vis spectrophotometry. The stability constants for the binary and ternary complexes of norfloxacin were always higher than those found for ofloxacin and comparing the values obtained for the binary and ternary species (DeltalogK) it is possible to conclude that the ternary complexes are more stable than the binary ones, suggesting that an interaction occurs between the ligands in the ternary complexes. From the distribution diagrams it is possible to state that at physiological pH 7.4, the copper ternary complexes, are the main species in solution not only at the concentration used to determined the stability constants but also at the minimum inhibitory concentration. The antibacterial activity of these complexes, in different bacterial strains, was determined, at physiological pH, and the results obtain show that these ternary complexes may be good candidates as metalloantibiotics.

Synthesis and antibacterial activity of nitroaryl thiadiazole-levofloxacin hybrids.

Novel levofloxacin-containing hybrids carrying a 5-(nitroaryl)-1,3,4-thiadiazol-2-yl group were synthesized and evaluated in vitro against Gram-positive and Gram-negative bacteria. Preliminary data indicated that levofloxacin-nitrofuran and levofloxacin-nitroimidazole hybrids have a potent activity against Gram-positive organisms with enhanced anti-staphylococcal activity compared with the parent quinolone (N-desmethyl levofloxacin).

Synthesis and biological testing of non-fluorinated analogues of levofloxacin.

Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.

Synthesis and anti-HIV activity of arylpiperazinyl fluoroquinolones: a new class of anti-HIV agents.

Synthesis and anti-HIV activity of a series of novel arylpiperazinyl fluoroquinolones are reported. In the SAR study, the aryl substituents on the piperazine nitrogen were found to play an important role for the anti-HIV-1 activity. A few of the compounds exhibited potent anti-HIV activity: IC50=0.06 microM in chronically infected cells.

[A new practical route to stereospecific synthesis of (S)-(-)-ofloxacin].

(S)-(-)-ofloxacin is one of the best fluoroquinolone agents in current clinical use. A new facile practical route with good yield and high optical purity to stereospecific synthesis of (S)-(-)-ofloxacin was described.

Effects of aluminium-containing antacid on bioavailability of ofloxacin following oral administration of pivaloyloxymethyl ester of ofloxacin as prodrug.

We newly synthesized a pivaloyloxymethyl ester of ofloxacin (OFLX-PVM) as prodrug in order to avoid the chelate formation between new quinolone and metal cations such as Al3+, Mg2+, Ca2+, or Fe2+ in the gastrointestinal tract. This compound was rapidly hydrolyzed in an incubation experiment by 43% in plasma, by 92% in small intestinal mucosal homogenates, and by 97% in liver homogenates during 0.5 h incubation, but was resistant to hydrolysis by pancreatic enzymes. In everted gut sac experiments, this compound was efficiently absorbed even in the presence of aluminium ion, whereas the absorption of ofloxacin (OFLX) was decreased significantly by the presence of aluminium ion. Minimal inhibitory concentration (MIC) values of OFLX-PVM were far higher than OFLX. Effects of aluminium hydroxide on the oral bioavailability of OFLX and OFLX-PVM were investigated in rabbits. The area under the plasma concentration-versus-time curve from zero to 24 h (AUC0-24h) following oral administration of OFLX was decreased significantly by 47.6% by combined administration with aluminium hydroxide, but AUC0-24h values of OFLX-PVM coadministered with and without aluminium hydroxide were similar to that of OFLX alone. These observations indicate that this new compound is likely to offer a prodrug for avoidance of interaction between new quinolone and metal cations.

Novel 1-8-bridged chiral quinolones with activity against topoisomerase II: stereospecificity of the eukaryotic enzyme.

A series of novel C-7 quinolyl-substituted enantiomers of ofloxacin were used to determine the stereospecificity of topoisomerase II for the C-11 methyl group in tricyclic quinolones. In all cases, the S isomer was the most active compound against the eukaryotic enzyme. It was approximately 2.2-fold more potent than the R isomer at inhibiting the overall catalytic activity of topoisomerase II (as monitored by DNA relaxation assays). A markedly greater difference in quinolone activity was observed in enzyme-mediated DNA cleavage reactions. While the S enantiomer stimulated nucleic acid breakage approximately 3.5-fold, the R compound did not enhance and, in fact, decreased initial DNA cleavage levels by approximately 50%. The activity of the racemic mixture more closely resembled that of the R enantiomer. In competition experiments, the DNA cleavage-enhancing effects of the S isomer were attenuated by the R compound. Taken together, these latter results indicate that the R enantiomer is an antagonist of S isomer-promoted topoisomerase II-mediated DNA cleavage. Finally, the cytotoxic potential of quinolyl-substituted ofloxacin analogs correlated with the ability to stimulate enzyme-mediated DNA cleavage. Thus, stereochemistry appears to be a governing factor for the potential development of tricyclic quinolones as topoisomerase II-targeted drugs with antineoplastic activity.

Synthesis and antipseudomonal activities of some ofloxacin esters as prodrugs.

Three new ofloxacin esters have been synthesized as prodrug by the reaction of ofloxacin (CAS 82419-36-1) with chloromethylacetate, 1-chloroethylacetate and 1-chloroethylethylcarbonate in acetonitrile. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, Mass spectra and elementary analysis. In vitro activities of these compounds against clinical isolates of various Pseudomonas aeruginosa species have been determined by microtiter tube dilution method, and octanol/water partition coefficients and pH dependent hydrolysis rates have been investigated in comparison with ofloxacin.

New "ofloxacin" type antibacterial agents. Incorporation of the spiro cyclopropyl group at N-1.

The first example incorporating a spiro cyclopropyl group into an "ofloxacin" type of quinolone antibacterial agent has been prepared by potassium fluoride mediated ring closure of the hydroxymethyl cyclopropyl intermediate to give 9'-fluoro-7'-oxo-10'-(1-piperazinyl)spiro[cyclopropane-1,3'(2'H)-[7H] pyrido[1,2,3-de][1,4]benzoxazine]-6'-carboxylic acid. Analogues were made by substitution at C-7 by various complex amines. Evaluation of these compounds for antibacterial activity was carried out. All examples prepared and examined showed in vitro minimum inhibitory values and in vivo mouse protection results to be diminished as compared to the parent, ofloxacin.