Mazzone G

Synthesis and biological evaluation of thiazolo-triazole derivatives

Abstract Two series of isomeric thiazolo[3,2-b][1,2,4]triazole and thiazolo[2,3-c][1,2,4]triazole derivatives were prepared following multiple synthetic pathways. The obtained compounds were submitted to preliminar pharmacological assays to evaluate their anti-inflammatory, analgesic and antipyretic activity. Suggestions about structure-activity relationships between the two classes of isomers were delineated. Moreover, some of the starting molecules, phenacylthio[1,2,4]triazoles were submitted to microbiological analysis to test their antibacterial and antimycotic activity.

Formulation parameters of fluoroquinolone-loaded liposomes and in vitro antimicrobial activity☆

Abstract To load pefloxacin and ofloxacin in liposomes, two preparation procedures were carried out, leading to the formation of multilamellar vesicles (MLVs) or reverse-phase evaporation vesicles (REVs). MLVs were able to entrap greater amounts of the two drugs than REVs, especially when the drugs were co-dissolved with the lipid mixture in the organic phase. The encapsulation efficiency was influenced by the presence of a negatively charged lipid in the liposome composition: the greater the content of charged lipidic compound, the larger is the amount of drug entrapped. Among the charged systems, a dipalmitoylphosphatidylcholine-cholesterol-dihexadecyl phosphate mixture (4:3:4 molar ratio) showed the highest trapping capacity. The fluidity of the bilayer could also influence the encapsulation efficiency. In fact, the increase in encapsulation capacity for the lecithin-cholesterol-dihexadecyl phosphate mixture (4:3:4 molar ratio) conformed to the following order: dipalmitoylphosphatidylcholine > dimyristoylphosphatidylcholine > egg phosphatidylcholine. Variation in pH values led to different encapsulation efficiency and release rate. In vitro experiments on the antimicrobial activity of the encapsulated fluroquinolones compared to the free drug demonstrated a reduction of at least 50% of the minimal inhibitory concentration.

A physico-chemical study on the interaction between papaverine and natural and modified β-cyclodextrins

The interaction of the alkaloid drug papaverine (PAP) with different cyclodextrins (CyDs) was investigated. Freeze-drying method was used to prepare solid complexes that were characterized in the solid state using differential scanning calorimetry (DSC) and X-ray diffractometry. Circular dichroism spectroscopy (CD) and 1H-NMR was used in an aqueous solution to obtain information about the inclusion mode of PAP into the cavity of CyDs. β-cyclodextrin (β-CyD) and dimethyl-β-cyclodextrin (DM-β-CyD) are able to include the drug but in all cases the stability constant values are very small, indicating a weak host–guest interaction. No exact information exists about the interaction of PAP with the internal cavity of hydroxypropyl-β-cyclodextrin (HP-β-CyD). Solubility studies in the presence of all CyDs were performed using Higuchi and Connors methods at 37°C and pH 7.4. The influence of complexation on the diffusion rate of PAP through artificial membranes was evaluated using dialysis bags. Little influence was observed in the presence of all macrocycles.

Inclusion Complexation of 4-Biphenylacetic Acid with β-Cyclodextrin

AbstractThe preparation of an inclusion complex of 4-biphenylacetic acid (BPAA), a non-steroidal antiinflammatory drug, with β-cyclo-dextrin is described. The presumible structure of the inclusion system, the molar ratio, which was found 1:1, and the formation constant were calculated by the analysis of IR, UV, DSC, X-ray diffraction, and 1H-NMR. Dissolution rate and solubility were also studied. BPAA solubility in water resulted significantly (4,2-fold) increased by complexation, such as its dissolution rate which appears, in the first 12 min, 18 times greater for the complex than the drug alone.

Inhibition of rat liver mitochondrial monoamine oxidase by hydrazine-thiazole derivatives: structure-activity relationships.

The purpose of this research is to study the relationship between chemical structure and inhibitory activity of some hydrazine-thiazole derivatives on rat liver mitochondria monoamine oxidase (MAO). Forty-five compounds belonging to three series of hydrazine-thiazole derivatives, with either alkylic or arylic substituents in the thiazole ring, were tested. The highest inhibitory activity was observed with piperonyl derivatives 25 and 40, which contain a 4-methyl group in the thiazole nucleus. The structure-activity relationship of MAO inhibitors was established in relation to hydrophobic, electronic and steric hindrance parameters. A mechanism of enzyme inhibition was proposed based on the calculation of HOMO energies.

Cdp-Choline Entrapment and Release from Multilamellar and Reverse-Phase Evaporation Liposomes

AbstractIn this work it was reported the determination of CDP-choline entrapment efficiency in MLVs liposomes constituted of neutral or negatively charged phospholipids. The encapsulation capacity (EC) increases with using charged phospholipids; moreover, also the presence of cholesterol into the vesicle bilayers enhances the EC values, Liposomes, prepared with reverse—-phase evaporation method, entrapped greater amounts of drug than multilamellar liposomes of the same composition, The size of liposomes so like as the polidispersity index values were determined by light scattering analysis;. The rate of CDP-choline efflux from liposomes was determined “in vitro” and was dependent upon bilayer composition and the method of preparation.

Calorimetric studies on tolmetin release from poly-DL-lactide microspheres to lipid model membrane

Abstract The aim of this work was to study the rate of release of an NSAI agent from poly- dl -lactide (PDLLA) microspheres, by evaluating the effect of the drug on the thermotropic behaviour of dimyristoylphosphatidylcholine liposomes (DMPC), selected as a model membrane. Polylactide microspheres loaded with 1-methyl-5- p -toluoylpyrrole-2-acetic acid (tolmetin) were prepared by the spray-drying method. Samples made of liposomes charged with free drug and suspensions of blank liposomes added to weighed amounts of tolmetin-loaded microspheres were analyzed by DSC. Calorimetric analyses were performed on samples previously incubated at temperatures below and above the polymer glass transition temperature ( T g ). Free drug was found to interact with the phospholipidic bilayer by modifying its thermotropic behavior. The amount of drug released from the microparticulate to void liposomes was quantified by comparing the T m shift caused by drug release from the polymeric system with that due to free drug. The results demonstrate the extent to which the release process is affected by temperature throughout the polymeric structure. In conclusion, the calorimetric technique detects changes occurring directly on the adsorption sites and can thus be applied to study slow kinetics directly at the site of drug uptake.

Partitioning and differential scanning calorimetry studies of N-alkyllactame ester dermal prodrugs of indomethacin

Abstract The mechanism of indomethacin percutaneous absorption enhancement by N-alkyllactam ester prodrugs (esters I-III) was investigated by assessing stratum corneum partitioning and solubility together with diffusion parameters of both indomethacin and its prodrugs. Skin diffusional characteristics of indomethacin and its esters were evaluated on the basis of their apparent diffusion coefficients and their interaction, assessed by differential scanning calorimetry, with multilamellar liposomes of dipalmitoylphosphatidylcholine. From the results obtained, the enhancement ability of esters I and II could be attributed to their greater stratum corneum solubility associated with better diffusion characteristics compared to the parent drug, while the enhancement effect of ester III could be due only to its higher diffusion coefficient.

Synthesis and biological evaluation of some 5-aryl-2-amino-1,3,4-oxa(thia)diazoles.

Three series of 5-aryl-2-amino or 2-amino substituted 1,3,4-oxadiazoles (IV-XVIII) were prepared together with the corresponding series of the analogous 5-aryl-2-amino-1,3,4-thiadiazoles (XIX-XXXIII). The purpose of this work is two-fold: to study their pharmacological action in relation to the substituents bound to the positions -2 and -5, and to observe whether the isosteric substitution of the oxygen of he oxadiazolic nucleus with the sulfur leading to a thiadiazolic nucleus causes any activity variation. The AA. report and discuss the results obtained studying the antifungal as well as the antiinflammatory and antipyretic activity of the synthetized compounds.

METHOTREXATE INTERACTION WITH A LIPID MEMBRANE MODEL OF DPPC

Dipalmitoylphosphatidylcholine (DPPC) liposomes were employed as membrane models for the investigation of the interaction occurring between methotrexate (MTX) and bilayer lipid matrix. Liposomes were obtained by hydrating a lipid film with 50 mM Tris buffer (pH 7.4). The differential scanning calorimetry (DSC) evaluation of the thermotropic parameters associated with the phase transitions of DPPC liposomes gave useful information about the kind of drug-membrane interaction. The results showed an electrostatic interaction taking place with the negatively charged molecules of MTX and the phosphorylcholine head groups, constituting the outer part of DPPC bilayers. No interaction with the hydrophobic phospholipid bilayer domains was detected, revealing a poor capability of MTX to cross through lipid membranes to reach the interior compartment of a lipid bounded structure. These findings correlate well within vitro biological experiments on MTX cell susceptibility.ZusammenfassungDipalmitoylphosphatidylcholin (DPPC) Liposome wurden als Membranmodelle zur Untersuchung der Wechselwirkung zwischen Methotrexat (MTX) und doppelschichtigen Lipidmatrizen angewendet. Die Liposome erhielt man durch Hydratation eines Lipidfilmes mit 50 mM Tris-Puffer (pH 7.4). Die DSC-Auswertung der mit der Phasenumwandlung der DPPC-Liposome zusammenhängenden thermotropischen Parameter lieferte nützliche Informationen über die Art der Wechselwirkung zwischen Droge und Membran. Die Ergebnisse zeigten eine elektrostatische Wechselwirkung zwischen negativ geladenen Molekülen von MTX und den Phosphorylcholin-Endgruppen, die den äußeren Teil der DPPC-Doppelschichten bilden. Eine Wechselwirkung mit den hydrophoben Phospholipid-Doppelschichtregionen konnte nicht beobachtet werden, was auf eine geringe Fähigkeit von MTX zur Durchdringung der Lipidmembranen hinweist. Diese Resultate stehe in guter Übereinstimmung mit biologischenin vitro Versuchen zur MTX-Zellsuszeptibilität.