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A series of 2-hetaryl-4-fluoro-9-cyclopropyl-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylic esters (3a–f) and their corresponding acids4a–fhave been preparedviamicrowave-assisted cyclocondensation reaction with some hetarene carboxaldehydes. The structures for these new esters and acids are based on spectral (IR, MS, and NMR) data. Thein vitroantimicrobial assay of4a–fhetaryl derivatives, their aryl analogues1d–g, and the imidazo-unsubstituted acid1ashowed that all of these tricyclic heterocycles possess a good level of antibacterial activity. Among them, compound1aexhibited the highest effect against both, Gram-positive (minimum inhibitory concentrations [MICs] 0.15–3.0 μg mL–1) and Gram-negative bacteria (MICs 0.7–3.0 μg mL–1). An excellent activity was recorded also for the halo-phenyl derivatives1f,gand for the furan derivatives4e,f, especially toward Gram-positive strains andBacillus subtilisandHaemophilus influenzae, respectively.

Four novel ligands derived from 2,3-butanedione have been synthesized, two dissymmetric thiosemicarbazone/3-hydroxy-2-naphthohydrazone ligands, H2L1 (bearing 4-isopropyl-3-thiosemicarbazone) and H2L2 (containing 4-cyclohexyl-3-thiosemicarbazone) and the symmetric H2L3, diacetyl bis(3-hydroxy-2-naphthohydrazone), and H2L4, diacetyl bis(4-cyclohexyl-3-thiosemicarbazone). Their reactivity with SnR2Cl2 (R=methyl, n-butyl and phenyl) was explored and the resulting complexes were characterized by elemental analysis, molar conductivity, mass spectrometry, IR, 1H, 13C and 119Sn NMR and seven of them also by single crystal X-ray diffraction. The results showed that the reactivity of the dissymmetric ligands is strongly different and while the cyclohexyl derivative is very stable, with isopropyl easily undergoes a symmetrization reaction to yield the corresponding symmetric ligands. The antimicrobial activity of the ligands and the corresponding diorganotin(IV) complexes was investigated in vitro against seven species of microorganisms and minimum inhibitory concentrations (MICs) were determined. The results showed that the ligand H2L2 and several of its derivatives, together with methyl and phenyl complexes of H2L1, have the ability of inhibiting the growth of tested bacteria and fungi to different extents. Bacillus subtilis and Staphylococcus aureus Gram positive strains were the most sensitive microorganisms.

Some first row transition metal(II) complexes of imidazole-2-carbaldehyde semicarbazone (H2L) have been synthesised and characterised. Single crystal X-ray diffraction studies have revealed the molecular structure of the neutral complex NiCl2(H2L)(H2O). This latter complex shows a pseudo-octahedral geometry, with both chloride ions displaying a cis disposition. The asymmetry of this complex allows the formation of two enantiomers in the racemic crystal structure. The non-deprotonated semicarbazone ligand behaves as an N,N,O-donor, through the imidazole and imine N atoms and the Oketo atom. The coordinative behaviour of H2L in CuCl2(H2L)(H2O), ZnCl2(H2L)2·0.5EtOH and CoCl2(H2L)2·0.5H2O is reported as only N,O-donor. The antimicrobial activity of the semicarbazone ligand and its metal complexes has been tested against some representative bacteria and fungi. A moderate inhibitory activity of the cobalt complex was detected towards the assayed phytopathogenic fungi Alternaria tenuis and Sclerotinia minor (MIC 50 μg/mL).

We report on the synthesis and the antimicrobial activity of 9-cyclopropyl-4-fluoro-6oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acid (16), representative of a new class of antibacterial agents structurally related to the clinically successful fluoroquinolones. The novel 6-fluoroquinolone (16) is herein prepared, in good yield, by thermal cyclocondensation of ethyl 7,8-diamino-9-cyclopropyl-4-fluoro-6-oxoquinoxaline-7-carboxylate with thionyl chloride, followed by acid-catalysed hydrolysis of the ester intermediate (15). Their structures were characterized by IR, MS, 1 H- and 13 C NMR spectra and X-ray crystal structure of 16 is presented. The antimicrobial evaluation against a broad panel of wild and resistant Grampositive and Gram-negative bacteria and fungal species demonstrated the high antibacterial activity of 16, even at the concentration of 0.015 µg mL -1 .

Cobalt(II), nickel(II), copper(II) and zinc(II) complexes of 2-thiophenecarbonyl hydrazone of 3-isatin (H2L 1 ) and 2-furoic hydrazones of 3-isatin (H2L 2 ) and 3-(N-methyl)isatin (HL 3 ), with general composition [M(L)2]� nX, where X is ethanol or/and water, were synthesised and characterised. The molecular structure of HL 3 showed that it crystallised in the keto form, which is also the more abundant tautomer for the three hydrazone ligands in solution. The three ligands behave as j 2 -O,N donors in the cobalt(II) and zinc(II) complexes. The X-ray crystal structure of pseudotetrahedral [Zn(HL 1 )2]� 1.75MeOH confirmed the O,N coordination mode of the two monodeprotonated ligands in their keto forms. Secondary interactions of zinc ions with the O atoms of each isatin keto residue provoke a substantial distortion towards a square pyramidal form. The interaction of the isatin keto residues is stronger in the three nickel(II) complexes where the three acylhydrazones can be considered as j 3 -O,N,O donors.

Novel hybrid molecules between benzenesulfonamides and active antimicrobial 2-amino-benzo[ d ]isothiazol-3-ones were synthesized and characterised and their in vitro antimicrobial activity was evaluated by the minimal inhibitory concentration (MIC). The compounds exhibit moderate antibacterial properties against Gram-positive bacteria (MIC 6–100 μg ml −1 ) such as several bacilli, staphylococci and streptococci, including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains, while no inhibition of Gram-negative Escherichia coli is detected up to the concentration of 100 μg ml −1 . Synergistic inhibitory activity occurs when sulfanilamides 4a and 4c are tested in combination with trimethoprim against S. aureus . Concerning antifungal properties, only compound 4c is able to inhibit the growth of Saccharomyces cerevisiae and Cryptococcus neoformans yeasts and several dermatophytes. Structure–activity relationships are discussed.

Several thiazoles and benzothiazoles carrying a benzenesulfonamide moiety at position 2 of the heterocyclic nucleus were synthesised and tested as antimicrobial agents. All sulfanilamides and some of the nitro substituted sulfonamides have effective antibacterial properties against Gram positive bacteria (MIC 0.3-100 µg/mL) such as several bacilli, staphylococci and streptococci, including methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis strains. On the contrary, no inhibition of Gram negative Escherichia coli and fungi is detected up to the concentration of 100 µg/mL. Synergistic inhibitory activity occurs when the active antibacterial sulfonamides are tested in combination with trimethoprim against both Bacillus subtilis and Staphylococcus aureus.

Nicotinamide is a hydrophilic molecule, freely soluble in water, used as cosmetic active ingredient for its moisturizing and depigmenting properties. Moreover it has the ability to augment the solubility of poorly water-soluble molecules acting as a hydrotrope. The aim of this work was to study the effect of nicotinamide on the transdermal permeation of methyl, ethyl, propyl and butyl paraben. Parabens flux was measured in vitro in the presence and absence of different amounts of nicotinamide. From solubility studies it was found that nicotinamide forms one or more complexes with methyl, propyl and butyl paraben in water, even though with low stability constants. The interaction of ethyl paraben seems to be less easy to explain. The association of nicotinamide with parabens causes a significant reduction of the permeability coefficients of these preservatives through rabbit ear skin, caused by a reduction of the stratum corneum/vehicle partition coefficient. The effects of nicotinamide on parabens solubility, permeation and partitioning are potentially very interesting because nicotinamide can facilitate paraben dissolution in aqueous media (solutions, gels), reduce parabens partitioning in the oily phase thus guaranteeing an effective concentration in the water phase in emulsion and reduce transdermal penetration, thus reducing the toxicological risk.

All new quinolone derivatives (IV) show antibacterial activities higher than the reference drug ciprofloxacin, both towards Gram positive Bacillus subtilis and Staphylococcus aureus, and Gram negative Haemophilus influenza strains.

New 2-thiazolylimino-5-arylidene-4-thiazolidinones (compounds 4a-j), unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesized and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The compounds were very potent towards all tested Gram positive microorganisms (MIC ranging from 0.03 to 6 microg/mL in most of the cases) and Gram negative Haemophilus influenzae (MIC 0.15-1.5 microg/mL), whereas no effectiveness was exhibited against Gram negative Escherichia coli and fungi up to the concentration of 100 microg/mL. The 5-arylidene derivatives showed an antibacterial efficacy considerably greater than that of the parent 2-(thiazol-2-ylimino)thiazolidin-4-one 3, suggesting that the substituted and unsubstituted 5-arylidene moiety plays an important role in enhancing the antimicrobial properties of this class of compounds. The remarkable inhibition of the growth of penicillin-resistant staphylococci makes these substances promising agents also for the treatment of infections caused by microorganisms resistant to currently available drugs.

Copper complexes of thiosemicarbazones of imidazole-2-carbaldehyde, pyrrole-2-carbaldehyde and indole-3-carbaldehyde were synthesised and characterised. The antimicrobial properties of the free ligands and their complexes were evaluated against yeasts, moulds and bacteria (Gram-positive and Gram-negative). Some copper chelates exhibited a moderate inhibitory activity, better than that of the corresponding free ligands. In particular, the pyrrole derivative [Cu(HL(2))(2)] proved to be a wide spectrum agent, showing an interesting inhibition of the growth of all Gram-positive bacteria and fungi tested at concentrations of 12-50 microg/mL. In contrast, a selective effect was observed for imidazole and indole chelates against fungi and Gram-positive bacteria, respectively.

Ni(II), Co(II) and Co(III) complexes of imidazole- and pyrrole-2-carbaldehyde thiosemicarbazone ligands (H2L1 and H2L2, respectively) have been prepared. The X-ray crystal structures of [Co(L1)(HL1)], [Ni(H2L1)2]Cl2 · 3.5H2O and [Ni(HL2)2] have been solved. The Co(III) ion assumes a slightly distorted octahedral coordination geometry, involving both N2S binding domain of di- and monoanionic ligand molecules. Whereas in [Ni(HL2)2] the metal ion is tetracoordinated in a square planar geometry by two pyrrole-2-carbaldehyde thiosemicarbazone molecules acting as NS-donor, the spatial array of non deprotonated H2L1 ligand molecules in [Ni(H2L1)2]Cl2 · 3.5H2O is equivalent to that found for [Co(L1)(HL1)]. The in vitro antimicrobial properties of the ligands and their complexes were tested against representative bacterial and fungal strains in broth culture. The compounds H2L2 and [Co(L2)(HL2)(H2L2)] · 1.5H2O exhibit a moderate inhibitory effect on the microbial proliferation and only against some Gram positive bacteria.

The aim of this work was to study the skin distribution of 5-methoxypsoralen (5-MOP) after application of topical gels, in vitro and in vivo, in both healthy and psoriatic skin sites of 6 psoriatic patients. Drug skin distribution was determined using the thin slicing technique and subsequent HPLC analysis. In the presence of dermatological disease, i.e. psoriasis, the permeability of the tissue changed considerably, leading to an important increase in the cumulative amount of 5-MOP recovered in the skin after topical application. The amount of 5-MOP found in vitro in the human skin was intermediate between those cumulated in healthy and psoriatic skin sites during an in vivo experiment. The gel formulation is an efficacious carrier for the topical photochemotherapy of psoriasis with 5-MOP, since it allows drug penetration in psoriatic skin.

A series of hydrazones of 1,2-benzisothiazole hydrazides 1a-m, 2a-m, 3a-m, 4a-m, 5a-m as well as their cyclic (1 and 4) and acyclic (2, 3 and 5) 1,2-benzisothiazole parent hydrazides, were synthesised and evaluated as antibacterial and antifungal agents. All of the 2-amino-1,2-benzisothiazol-3(2H)-one derivatives, belonging to series I and IV, showed a good antibacterial activity against Gram positive bacteria. Most of them were active against yeasts too. Compounds 1 and 4, together with 1l, proved to be the most effective compounds. Quantitative structure-activity relationship (QSAR) investigation with a 2D-QSAR analysis was applied to find a correlation between different experimental or calculated physicochemical parameters of the compounds studied. A 3D-QSAR study was performed, applying Comparative Molecular Similarity Indices Analysis (CoMSIA) method, to derive quantitative models relating the structural features of 1,2-benzisothiazole derivatives 1, 1a-m and 4, 4a-m and their antimicrobial activity against Bacillus subtilis, resulted the most sensitive micro-organism.

A series of 7-aryl-6-fluoro-8-nitroquinolones ( 6a – e ) were synthesized through a novel, simple and clean synthetic procedure, through a Suzuki–Miyaura reaction. The target compounds were evaluated in vitro for their antimicrobial properties against bacterial and fungal strains. All of them showed antibacterial activity higher than the activity of ciprofloxacin, both towards Gram positive Bacillus subtilis and Staphylococcus aureus , and Gram negative Haemophilus influenzae strains. Compound 6d , containing the trisubstituted 7-aryl moiety, emerged as the most active quinolone derivative with MIC values ranging from 0.00007 μg/mL to 0.015 μg/mL.

New 9-(alkyl/aryl)-4-fluoro-6-oxo[1,2,5]thiadiazolo[3,4-h]quinoline-5-carboxylic acids and their esters were designed and synthesized. A detailed discussion of the reactions utilized in the preparation of the intermediate and target compounds is reported. All the newly synthesized compounds were fully characterized using all the physico-chemical means needed. All the intermediates and the final esters and acids were tested against bacterial and fungal strains. The acids 25a and 25c proved to be very active against Gram positive and Gram negative bacteria with MIC 0.15-3 µg/mL. The structure-activity relationship of antibacterial thiadiazoloquinolones shows that compounds 25a and 25c are twice less potent than the corresponding cyclopropyl derivative 16. Therefore, the cyclopropyl moiety on N-9 seems to be the most suitable substituent.

The antimicrobial properties of N-(2-hydroxyethyl)-1,2-benzisothiazol-3(2H)-thione (1a,b) and its carbamic esters 2a,b-6a,b were tested in vitro against Gram positive and Gram negative bacteria, yeasts and dermatophytes. All compounds markedly inhibit the growth of Gram positive bacteria exhibiting MIC values ranging from 1.25 to 10 micrograms/ml. A strong antifungal activity is exerted against dermatophytes with MICs, in general, between 0.7 and 12 micrograms/ml. Structure-activity relationship studies show that these compounds are, in most cases, more effective than the corresponding benzisothiazolone analogues 7-12. None of the tested compounds shows genotoxic properties by Bacillus subtilis rec-assay and Salmonella-microsome test.

Mono- and bimetallic organotin complexes with pyrrole-2,5-dicarboxaldehyde bis(2-hydroxybenzoylhydrazone) (H 5 dfps) and pyrrole-2,5-dicarboxaldehyde bis(2-picolinoylhydrazone) (H 3 dfpp) were synthesized and characterized by IR, 1 H and 119 Sn NMR spectroscopy. X-ray analysis of the complex [Sn(H 3 dfps)(C 6 H 5 ) 2 ] · (CH 3 ) 2 SO revealed a pentacoordination around tin through a N,N,O terdentate ligand behaviour of the hydrazone. This complex is the most active compound, exhibiting MIC values of 3 and 12 μg/ml against Gram positive and Gram negative bacteria, respectively. None of the ligands or complexes produced DNA-damage in the Bacillus subtilis rec -assay or showed mutagenic activity in the Salmonella -microsome test.

Glucocorticosteroids, a class of drugs widely used in the treatment of allergies, airways inflammation and inflammatory ocular diseases, are often difficult to sterilize due to their inherent sensibility to heat or irradiation induced degradation. Being often in form of suspension, obviously the final medicinal product cannot be sterilized by filtration. The effectiveness of supercritical CO 2 (SC-CO 2 ) based method for the sterilization of food and biomedical materials is well documented in the literature. Few reports are available on the sterilization of drugs especially in powder form with SC-CO 2 . The aim of the present work was to investigate the suitability of SC-CO 2 at mild temperature for the decontamination of two model corticosteroid powders (beclometasone dipropionate and budesonide) both in dry or wet form. We found that SC treatment in wet environment reduces by at least six orders of magnitude the contamination of micronized steroidal drugs while retaining the particle size distribution. The findings of this work are of particular interest for the application in the case of aqueous suspension of steroids for aerosol therapy or ocular delivery, where the sterilization process with SC-CO 2 could be carried out directly on the bulk of the final formulation.

This paper reports the synthesis and the insecticidal activities of some N-benzoyl-N'-arylureas 4-arylsubstituted with alkylated or halogenated aroyl moieties. The compounds, tested against some representative insect species, displayed very high activity against Aedes aegypti, especially the halosubstituted derivatives. None of the newly synthesized compounds showed genotoxic activity in the Bacillus subtilis rec-assay and in the Salmonella-microsome test.

The ligand behavior of di-2-pyridylketone 2-aminobenzoylhydrazone (Hdpa), and phenyl(2-pyridyl)ketone 2-aminobenzoylhydrazone (Hdpa) towards organotin derivatives was investigated. The synthesis and the IR and 119Sn NMR spectroscopic characterization of the compounds is reported, together with the X-ray crystal structures of Hdpa and Sn(C6H5)3Cl(OH2)·Hdpa, which are discussed and compared. The in vitro evaluation of antimicrobial properties revealed the strong activity of Sn(C6H5)2(Hdpa)Cl2 and Sn(C6H5)3Cl(OH2)·Hdpa complexes. None of the compounds showed genotoxicity in the Bacillus subtilis rec-assay and in the Salmonella-microsome test.

Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100ml maintained the positive zeta potential value of about + 45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20 mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively. © 2013 Elsevier B.V.

A facile synthesis of model 4-oxopyrido[3',2':4,5]thieno[3,2-b]indole-3-carboxylic acids 9a-e was achieved via Stille arylation of 2-chloro-3-nitro-4-oxothieno[2,3-b]pyridine-5-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. Compounds 9a-c and 9e exhibited very high potency against Gram positive Bacillus subtilis and Bacillus megaterium at concentrations 0.000015-0.007 μg/mL. They also displayed excellent activity towards other Gram positive bacilli and staphylococci and Gram negative Haemophilus influenzae, being in most cases superior or equal to commercial fluoroquinolones. Both 9a and 9c were inhibitors of the DNA gyrase activity. As concerns antitumor properties, compounds 9b-e showed growth inhibition of MCF-7 breast tumor and A549 non-small cell lung cancer cells with IC(50) 1.6-2.8 μM and 2.6-6.9 μM, respectively, coupled with absence of cytotoxicity towards normal cells. These compounds are promising as dual acting chemotherapeutics.

Several methyltin(IV) and butyltin(IV) complexes with the ligand benzil bis(benzoylhydrazone) and 4,4′-bipyridyl as coligand were synthesised and characterized by elemental analysis and by IR, 1H, 13C and 119Sn NMR spectroscopies. Some of them were also analyzed using single crystal X-ray diffraction. The title compounds were evaluated for their in vitro antimicrobial properties. All buthyltin complexes showed significant inhibition of Gram positive bacteria, resulting Bacillus subtilis, Sarcina lutea and both methicillin-susceptible and methicillin-resistant Staphylococcus epidermidis the most sensitive strains. Furthermore, they were able to inhibit the growth of Gram negative bacteria, especially Proteus vulgaris, whereas no activity was exhibited against fungi. All methyltin complexes were devoid of antimicrobial properties.

Three types of palladium(II) halide complexes of quinolinylaminophosphonates have been synthesized and studied. Diethyl and dibutyl [α-anilino-(quinolin-2-ylmethyl)]phosphonates (L1, L2) act as N,N-chelate ligands through the quinoline and aniline nitrogens giving complexes cis-[Pd(L1/L2)X(2)] (X═Cl, Br) (1-4). Their 3-substituted analogues [α-anilino-(quinolin-3-ylmethyl)]phosphonates (L3, L4) form dihalidopalladium complexes trans-[Pd(L3/L4)(2)X(2)] (5-8), with trans N-bonded ligand molecules only through the quinoline nitrogen. Dialkyl [α-(quinolin-3-ylamino)-N-benzyl]phosphonates (L5, L6) give tetrahalidodipalladium complexes [Pd(2)(L5/L6)(3)X(4)] (9-12), containing one bridging and two terminal ligand molecules. The bridging molecule is bonded to the both palladium atoms, one through the quinoline and the other through the aminoquinoline nitrogen, whereas terminal ligand molecules are coordinated each only to one palladium via the quinoline nitrogen. Each palladium ion is also bonded to two halide ions in a trans square-planar fashion. The new complexes were identified and characterized by elemental analyses and by IR, UV-visible, (1)H, (13)C and (31)P nuclear magnetic resonance and ESI-mass spectroscopic studies. The crystal structures of complexes 1-4 and 6 were determined by X-ray structure analysis. The antitumor activity of complexes in vitro was investigated on several human tumor cell lines and the highest activity with cell growth inhibitory effects in the low micromolar range was observed for dipalladium complexes 11 and 12 derived from dibutyl ester L6. The antimicrobial properties in vitro of ligands and their complexes were studied using a wide spectrum of bacterial and fungal strains. No specific activity was noted. Only ligands L3 and L4 and tetrahalidodipalladium complexes 9 and 11 show poor activities against some Gram positive bacteria.

Some 2-sulfonyl- and 2-acylderivatives of the 4,5-dichloro-3(2H)-pyridazinone were prepared in order to test their fungicidal activity. Interesting results, both in vitro and in vivo, were obtained in particular from the alkylsulfonyl-derivatives. Genotoxic activity of 3(2H)-pyridazinones was evaluated in vitro by the Bacillus subtilis rec-assay and the Salmonella-microsome reversion assay.

Some sulfonamide and sulfonylurea derivatives of unsubstituted and 5-methylsubstituted 1,2-benzisothiazole were studied in vitro for their antimicrobial properties against bacteria and fungi. Compounds 7 and 8 exhibited good antibacterial activity against Gram positive bacteria. A strong synergism was observed when their growth-inhibitory effect was assayed in combination with trimethoprim by using Bacillus subtilis and Staphylococcus aureus as test microorganisms. The antimycotic action of benzenesulfonylurea derivative 9 was very marked for Madurella mycetomatis and dermatophytes Epidermophyton floccosum, Microsporum gypseum and Trichophyton spp.. Structure-activity relations are discussed.

A series of organotin compounds obtained from the reaction of 2,6-diacetylpyridine nicotinoyl- and isonicotinoylhydrazones with tri- and diorganotin chlorides was investigated. The IR and 119Sn NMR spectroscopic characterization of all the compounds is reported, together with the x-ray crystal structure of [SnEt2(H2dapin')]2[SnEt2Cl3]Cl3 · 2H2O (H2dapin'= 2,6-diacetylpyridine bis(isonicotinoylhydrazone)). The main feature in this compound is the presence of a tin atom in both the complex ionic units. The coordination polyhedron is a pentagonal bipyramid in the cation and a trigonal bipyramid in the anion. Results are discussed concerning the in vitro evaluation of antimicrobial properties and genotoxic potential of the compounds described. In all cases the complexes show a reduced antimicrobial activity as compared to that of the corresponding organotin compound. Genotoxic properties of the ligands, detected in the Ames test, disappear in the complexes.

Conventional formulations of chlorhexidine usually provide short-term efficiency, requiring repeated applications to maintain antibacterial activity. Therefore, appropriate release system of chlorhexidine controlling local drug delivery would reduce the number of applications and enhance patient compliance. The aim of this study was to develop a controlled release system based on medical polyurethane for the local delivery of chlorhexidine diacetate (CDA). CDA-loaded polyurethane films (CDA-Films) and CDA-loaded polyurethane sandwiches (CDA-Sandwiches) were obtained by casting and solvent evaporation. The physico-chemical aspects of CDA-loaded polyurethane systems were investigated, and the crystalline state of CDA in the polymeric system was highlighted. CDA-Films exhibited appropriate mechanical properties for further applications. Drug release was measured in two different media: (i) distilled water and (ii) physiological saline solution to mimic in vivo conditions. Drug release studies were performed up to 11 days on CDA-Films and 29 days for CDA-Sandwiches. Release of CDA depended on drug loading and the structure of the system. In particular, release of CDA from the sandwich system followed zero-order kinetic. The release rate was significantly lower in physiological solution. Antibacterial studies were carried out on CDA-Films against Staphylococcus aureus and Staphylococcus epidermidis showing 35 days persisting antibacterial activity. In conclusion, the polyurethane-based system developed in this study is potentially useful as a local delivery system for CDA and could be used not only in surgery but also in dental and clinical applications. © 2009 Elsevier B.V. All rights reserved.

Cobalt, nickel, copper and zinc coordination compounds of two thiosemicarbazones with general composition ML(2) (L: monodeprotonated ligand corresponding to 2-acetyl-gamma-butyrolactone thiosemicarbazone, HL(1), and 2-furancarbaldehyde thiosemicarbazone, HL(2)) and also complexes with general composition MCl(2)(HL(2)) were synthesized (except [NiCl(2)(HL(2))] and [Co(L(2))(2)]). The interaction of CuCl(2) with HL(2) gave [CuCl(HL(2))], a copper(I) complex. The ligands and metal complexes were characterized by IR, (1)H and (13)C NMR spectroscopy, and magnetic susceptibility measurements. The crystal structure of [Ni(L(2))(2)]x 2dmso was determined and a trans-square planar coordination of the two kappa(2)-N,S chelate rings forming polymeric strips through H-bonds with dmso was observed. Actually, in all the reported complexes both ligands behaved as kappa(2)-N,S chelates, except in the case of [Co(L(1))(2)] in which HL(1) is tridentate kappa(3)-N,S,O. The antimicrobial properties of all compounds were studied using a wide spectrum of bacterial and fungal strains. The copper complexes of HL(2) were the most active against all strains, including dermatophytes and phytopathogenic fungi. Most of the studied compounds, especially [Cu(L(1))(2)], presented good activity against Haemophilus influenzae, a very harmful bacterium to humans.

2-Heteroarylimino-5-benzylidene-4-thiazolidinones, unsubstituted or carrying hydroxy, methoxy, nitro and chloro groups on the benzene ring, were synthesised and assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria, yeasts and mould. The antimicrobial activity of the 2-benzo[d]thiazolyl- and of the 2-benzo[d]isothiazolyl-imino-5-benzylidene-4-thiazolidinones is, on the whole, lower in comparison with the high activity detected for the derivatives of the 2-thiazolylimino-5-benzylidene-4-thiazolidinone class. Nevertheless most of the benzo[d]thiazole analogues display good inhibition of the growth of Gram positive bacilli and staphylococci, including methicillin-resistant Staphylococcus strains. Among the 2-benzo[d]isothiazole analogues a few derivatives show a strong and selective activity against bacilli. Moreover, it is worth noting that the replacement of the thiazole nucleus for the benzo[d]thiazole bicyclic system in the parent 2-(benzo[d]thiazol-2-ylimino)thiazolidin-4-one leads to significant antifungal properties against both yeasts and moulds, properties not shown by the analogous 2-thiazolyl- and 2-benzo[d]isothiazolyl-imino)thiazolidin-4-ones. The structure-activity relationship of 33 analogues possessing the 2-heteroarylimino-4-thiazolidinone structure is analysed through QSAR models.

Cobalt(II), nickel(II), copper(II) and zinc(II) complexes of 2-thiophenecarbonyl and isonicotinoyl hydrazones of 3-( N -methyl)isatin (HL 1 and HL 2 , respectively) were synthesized and characterized, being the crystal structures of HL 1 , HL 2 and [Ni(L 1 ) 2 ] · 2CHCl 3 elucidated by X-ray diffraction techniques. The in vitro antimicrobial activity of all these compounds was tested against several bacteria and fungi. HL 1 and its complexes exhibited a strong inhibition of the growth of Haemophilus influenzae (MIC 0.15–1.50 μg/mL) and good antibacterial properties towards Bacillus subtilis (MIC 3–25 μg/mL). The minimal inhibitory concentration (MIC) was defined as the lowest concentration of compound inhibiting the growth of each strain. The antibacterial effectiveness was confirmed against a number of Gram positive bacteria, including methicillin-resistant Staphylococcus aureus. Yeasts and moulds showed a low susceptibility, except the dermatophyte mould Epidermophyton floccosum that is inhibited at concentrations ranging from 6 to 50 μg/mL. In general, the antimicrobial activity of the thiophene derivatives was greater than that of the isonicotinic analogues.

A new series of ligands is synthesised starting from thiocarbonohydrazide and isatin (H(2)itc) or N-alkylisatin (methyl, H(2)mtc; butyl, H(2)btc; pentyl, H(2)ptc); the X-ray structure of H(2)mtc is discussed. The bis imine ligands are reacted with diorganotin(IV) compounds, obtaining monometallic complexes. In order to establish unequivocally their coordination geometry, the X-ray structures of (C(2)H(5))(2)Sn(Hmtc)Cl.THF (THF, tetrahydrofuran) and (C(6)H(5))Sn(Hptc)Cl(2) are determined. In (C(2)H(5))(2)Sn(Hmtc)Cl.THF, the ligand results monodeprotonated and, essentially, monodentate through the sulphur atom, while in (C(6)H(5))Sn(Hptc)Cl(2) the ligand is still monodeprotonated but SNO tridentate. The organotin(IV) complexes of isatin and N-methylisatin exhibit good antibacterial activity, better than that of the corresponding N-butyl and N-pentylisatin derivatives. Gram positive bacteria are the most sensitive microorganisms. No growth inhibition of fungi is detected up to the concentration of 100 microg/ml. H(2)mtc shows mutagenic activity with and without metabolic activation, whereas no mutagenicity is found for its organotin complexes and for the other compounds.

The in vitro antimicrobial activity of 2-amino-benzo[ d ]isothiazol-3-one and of several 2-arylideneamino derivatives carrying in the second position a substituted or unsubstituted aromatic ring or an arylalkenylidene moiety was determined by the broth dilution method against several strains selected to define their spectrum and potency. All the compounds demonstrated good antibacterial properties against Bacillus subtilis , streptococci, enterococci and staphylococci including penicillin-resistant clinical isolates. Several compounds showed excellent inhibitory properties against Streptococcus pyogenes , which is the most sensitive microorganism tested. Many benzisothiazolones exhibited good activity against Gram-negative Haemophilus influenzae . As regards antifungal activity, several of the tested compounds inhibited Saccharomyces cerevisiae at concentrations of 3–6 μg ml –1 . In all cases the parent 2-amino-benzo[ d ]isothiazol-3-one was the most effective agent, with minimum inhibitory concentration (MIC) values ranging from 0.07 to 6 μg ml –1 . The results obtained indicate that most of these compounds are wide-spectrum antimicrobial substances and promising agents against penicillin-resistant staphylococci.

In the present paper we evaluate the cellular toxicity of some N -substituted 2,2′-dicarboxamidodiphenyldisulphides with high antimicrobial activities, in view of their potential application in humans or animals. The toxicological studies have been conducted in the murine cell line of 3T3 fibroblasts as eucaryotic cellular model. Our results have allowed the identification of a series of derivatives exhibiting antimicrobial activity and low cellular toxicity. Structure–cytotoxic activity relationships are also discussed.

Several mono- and bis- carbono- and thiocarbonohydrazone ligands have been synthesised and characterised; the X-ray diffraction analysis of bis(phenyl 2-pyridyl ketone)thiocarbonohydrazone is reported. The coordinating properties of the ligands have been studied towards Cu(II), Fe(II), and Zn(II) salts. The ligands and the metal complexes were tested in vitro against Gram positive and Gram negative bacteria, yeasts and moulds. In general, the bisthiocarbonohydrazones possess the best antimicrobial properties and Gram positive bacteria are the most sensitive microorganisms. Bis(ethyl 2-pyridyl ketone)thiocarbonohydrazone, bis(butyl 2-pyridyl ketone)thiocarbonohydrazone and Cu(H 2 nft)Cl 2 (H 2 nft, bis(5-nitrofuraldehyde)thiocarbonohydrazone) reveal a strong activity with minimum inhibitory concentrations of 0.7 μg ml −1 against Bacillus subtilis and of 3 μg ml −1 against Staphylococcus aureus . Cu(II) complexes are more effective than Fe(II) and Zn(II) ones. All bisthiocarbono- and carbonohydrazones are devoid of mutagenic properties, with the exception of the compounds derived from 5-nitrofuraldehyde. On the contrary a weak mutagenicity, that disappears in the copper complexes, is exhibited by monosubstituted thiocarbonohydrazones.

Some sulfonamide and sulfonylurea derivatives of unsubstituted and 5-methylsubstituted 1,2-benzisothiazole were studied in vitro for their antimicrobial properties against bacteria and fungi. Compounds 7 and 8 exhibited good antibacterial activity against Gram positive bacteria. A strong synergism was observed when their growth-inhibitory effect was assayed in combination with trimethoprim by using Bacillus subtilis and Staphylococcus aureus as test microorganisms. The antimycotic action of benzenesulfonylurea derivative 9 was very marked for Madurella mycetomatis and dermatophytes Epidermophyton floccosum, Microsporum gypseum and Trichophyton spp.. Structure-activity relations are discussed.

A series of organotin complexes with pyrrole-2-carboxaldehyde 2-hydroxybenzoylhydrazone (H3mfps) and pyrrole-2-carboxaldehyde 2-picolinoylhydrazone (H2mfpp) was investigated. The IR, 1H, and 119Sn nuclear magnetic resonance spectroscopic characterization of all the compounds is reported and discussed in connection with the ligand behaviour of the hydrazone and the structure of the organotin complex. Complexes exhibit antibacterial properties higher than those of the corresponding ligands but they turn out to be less potent than the parent organotin compounds. Sn(H3mfps) (C6H5)2Cl2.2H2O and Sn(Hmfpp)(n-C4H9)2Cl are the most active antibacterial compounds showing MIC values between 3-6 micrograms/ml against Bacillus subtilis and Staphylococcus aureus and between 6-25 micrograms/ml against Escherichia coli; the first compound also strongly inhibits the growth of Aspergillus niger. All the ligands and complexes are devoid of DNA-damaging activity in the Bacillus subtilis rec-assay. H2mfpp and its complexes Sn(Hmfpp)(C2H5)2Cl and Sn3(Hmfpp)(mfpp) (C6H5)3Cl6 are shown by the Salmonella-microsome assay to be mutagenic substances in the presence of a metabolic activation system. The obtained results are discussed on the basis of structure-activity relationships.

A sodium benzoate-sorbic acid preservative system of a pharmaceutical product was proved effective against a wild strain of Pseudomonas cepacia, following the official method of the Italian and British Pharmacopoeias. However, this preservative system was ineffective against a challenge of Ps. cepacia wild strain cells grown in the unpreserved pharmaceutical product and on culture media different from those described by the Pharmacopoeias. The adaptive resistance of the wild strain of Ps. cepacia was not demonstrated with a laboratory strain (ATCC 25609). In contrast, p-hydroxybenzoate-based preservative systems proved to be efficient in protecting the pharmaceutical product against a challenge of wild and laboratory strains of Ps. cepacia grown in the different conditions described above. The results obtained suggest the usefulness, in the official methods for testing pharmaceutical preservatives, of using wild microbial strains isolated from the pharmaceutical environment. Metabolic adaptive responses, capable of affecting the antimicrobial sensitivity of wild micro-organisms used to challenge the preserved product, can be detected by using cells grown in the unpreserved pharmaceutical product.

Summary A number of 1-methyl-1 H -imidazole derivatives and some of their oxygenated products were synthesized. An HPTLC technique for following the oxidation reactions in the different experimental conditions used was applied. The X-ray crystal structures of 1-methyl-2-methylsulfanyl-5-nitro-1 H -imidazole, 2-methanesulfinyl-1-methyl-5-nitro-1 H -imidazole and 2-methanesulfonyl-1-methyl-5-nitro-1 H -imidazole were determined. The compounds obtained were investigated for antimycotic and genotoxic activities. The compounds tested were found to exert very low growth inhibition against yeasts and moulds. Moderate antifungal properties against dermatophytes were demonstrated for 5-nitro derivatives. 2-Methanesulfonyl-1-methyl-5-nitro-1 H -imidazole was the most active substance. All 5-nitroimidazoles were genotoxic in Bacillus subtilis rec -assay, Salmonella microsome test and in Saccharomyces cerevisiae mitotic segregation assay. Structure-activity relationships are discussed.

The effects of Glycyrrhiza glabra L. extract, glycyrrhizinic acid, 18 alpha- and 18 beta-glycyrrhetinic acids on the mutagenicity of the ethyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, and ribose-lysine Maillard model systems were investigated by using the Salmonella/microsome reversion assay. The protocol used allowed us to detect desmutagenic and antimutagenic activity and to avoid false positive results due to toxicity. For all the compounds tested, no desmutagenic activity was observed against ethyl methanesulfonate and N-methyl-N'-nitro-N-nitrosoguanidine; only Glycyrrhiza glabra extract showed antimutagenic activity against ethyl methanesulfonate. On using the ribose-lysine mutagenic browning mixture, the desmutagenic activities of the Glycyrrhiza glabra extract, glycyrrhizinic acid, 18 alpha- and 18 beta-glycyrrhetinic acids were observed. 18 beta-Glycyrrhetinic acid was the most active compound. Glycyrrhiza glabra extract also exhibited antimutagenic activity against ribose-lysine.

Genotoxic properties of essential oils from Anthemis nobilis L., Artemisia dracunculus L., Salvia officinalis L., Salvia sclarea L., Satureja hortensis L., Satureja montana L., Thymus capitatus L., Thymus citriodorus Schreb., Thymus vulgaris L., Citrus bergamia Risso, were studied with Bacillus subtilis rec-assay and Salmonella/microsome reversion assay. The essential oil of Artemisia dracunculus L. "Piemontese" turned out to be active in the rec-assay but not in the Salmonella test. DNA-damaging activity was demonstrated to be due to the estragol component of the oil. Advantages of the combined use of these two short-term microbial assays in genotoxic studies are discussed.

The aim of this paper was to study the effect of the granulate properties and tablet compression force on disintegrating force behavior in order to investigate the capability of the disintegrating force to characterize tablets that have the same composition but were manufactured in different conditions. Several tablets containing spironolactone in the external or internal granulated mixture of calcium carbonate and maize starch differing in particle size distribution, were prepared at 3 compression levels. The force developed by tablets during water uptake and disintegration was measured and plotted versus time. The curves obtained were analyzed by the Weibull equation in order to calculate the parameters characterizing the tablet disintegration kinetics. The disintegrating force time parameter, the maximum force developed, and the area under the curve were determined. In general, the reduction of time parameter value and/or the increase in maximum force developed corresponded to an acceleration in tablet disintegration. In addition, the area under the force curve increased in stronger tablets, monitoring in a sensitive way the tablet structural changes introduced by compression force. The results showed that the disintegrating force measurement can detect small changes in the structure of the tablet that cannot be discriminated by pharmacopoeia tests. The effect of manufacturing, in particular compression force, on tablet properties was quantified by the parameters of disintegrating force kinetics.

The aim of this work was to find a drying procedure for moist sucralfate gel capable of producing dried sucralfate gel that retains the original gel properties of bioadhesion, rheology, and micromeritics. Spray-drying and microwave-drying procedures were employed. Mannitol was used as a gel-protective substance during the drying processes. The spray drying of moist sucralfate gel gave rise to a powder whose water suspensions showed significantly reduced viscosity. The bioadhesion of spray-dried sucralfate gel was strongly reduced by drying. When mannitol was used as a gel protector, the spray-dried sucralfate in part maintained the original bioadhesion of moist sucralfate gel. The preparation of a dried sucralfate gel retaining the bioadhesion characteristics, avoiding the use of mannitol, was made possible using the microwave-drying procedure. The microwave-dried product possesses a granular morphology suitable for direct compression because it is a free flowing and strongly coherent granular powder.

Two organotin compounds [SnPh(dpt)Cl2](1) and [SnPh3Cl(OH2)]·Hdpt (2) (Hdpt = di-2-pyridylketone 2-thenoylhydrazone) have been synthesized and characterized by IR spectroscopy and X-ray diffraction. Hdpt behaves differently in the two compounds: it is deprotonated and ONN tridentate in 1 and uncoordinated in 2, where pairs of hydrogen-bonded [SnPh3Cl(OH2)] and Hdpt molecules are present. The tin environment is octahedral in 1 and trigonal bipyramidal in 2. Compound 2 has shown good antimicrobial activity against Gram-positive bacteria and moulds in vitro. Neither compound showed genotoxic properties.