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Recently, the cultivation of light Cannabis, with a total THC content less than 0.6%, has been encouraged due to its industrial and therapeutic potential. This has increased the consumption of hemp for both smoking purposes and food preparation. Even so, Cannabis inflorescences are not subject to EU regulations and standards provided for food and tobacco products. A study was carried out on thirty-one inflorescences samples, collected in different Italian regions, in order to determine cannabinoids, pesticides and metals and to evaluate the exposure of consumers to contaminants and ensure a safe consumption. Contents of THC were always below 0.5%, while CBD ranged between 0.3 and 8.64%. The determination of 154 pesticides showed that 87% of the samples contained fungicides and insecticides in the range 0.01–185 μg/g. The most found are spinosad and cyprodinil. The concentration of metals ranged from 1 to more than 100 μg/g and As, Cd, Co, Cr, Hg, Cu, Mo, Ni and V exceeded the regulatory US limits for inhaled Cannabis products, while Pb exceeded them for both oral and inhaled products. These contaminants are intrinsically toxic and may affect public health. Actions are needed to establish regulatory measures and reduce the adverse effects caused by contaminants in Cannabis.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for serious hospital infections worldwide and represents a global public health problem. Curcumin, the major constituent of turmeric, is effective against MRSA but only at cytotoxic concentrations or in combination with antibiotics. The major issue in curcumin-based therapies is the poor solubility of this hydrophobic compound and the cytotoxicity at high doses. In this paper, we describe the efficacy of a composite nanoparticle made of curcumin (CU) and graphene oxide (GO), hereafter GOCU, in MRSA infection treatment. GO is a nanomaterial with a large surface area and high drug-loading capacity. GO has also antibacterial properties due mainly to a mechanical cutting of the bacterial membranes. For this physical mechanism of action, microorganisms are unlikely to develop resistance against this nanomaterial. In this work, we report the capacity of GO to support and stabilize curcumin molecules in a water environment and we demonstrate the efficacy of GOCU against MRSA at a concentration below 2 µg ml(−1). Further, GOCU displays low toxicity on fibroblasts cells and avoids haemolysis of red blood cells. Our results indicate that GOCU is a promising nanomaterial against antibiotic-resistant MRSA.

Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for serious hospital infections worldwide and represents a global public health problem. Curcumin, the major constituent of turmeric, is effective against MRSA but only at cytotoxic concentrations or in combination with antibiotics. The major issue in curcumin-based therapies is the poor solubility of this hydrophobic compound and the cytotoxicity at high doses. In this paper, we describe the efficacy of a composite nanoparticle made of curcumin (CU) and graphene oxide (GO), hereafter GOCU, in MRSA infection treatment. GO is a nanomaterial with a large surface area and high drug-loading capacity. GO has also antibacterial properties due mainly to a mechanical cutting of the bacterial membranes. For this physical mechanism of action, microorganisms are unlikely to develop resistance against this nanomaterial. In this work, we report the capacity of GO to support and stabilize curcumin molecules in a water environment and we demonstrate the efficacy of GOCU against MRSA at a concentration below 2 µg ml −1 . Further, GOCU displays low toxicity on fibroblasts cells and avoids haemolysis of red blood cells. Our results indicate that GOCU is a promising nanomaterial against antibiotic-resistant MRSA.

The HIV-1 integrase (IN) and reverse transcriptase (RT) are essential enzymes in the virus cycle. RT is crucial for the retrotranscription of the RNA viral genome, while IN is involved in the insertion in host chromosome of the proviral double strand DNA produced by RT. This enzyme has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) and the ribonuclease H (RNase H). The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. Since the discovery that catalytic cores of both HIV-1 RNase H and IN are folded in a very similar way, have very similar active site geometries, and show the same DDE triad absolutely required for catalytic activity, some researches were devoted to study IN and RNase H dual inhibitor. Our decennial interest in design and synthesis of IN inhibitors led us to study the activity of our compounds also on RNase H activity. The results of the activities showed by pyrrolyl and quinolonyl diketo acids are reported and discussed.

The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV-1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action.

A simple and efficient strategy to convert the racemic mixture of 8-chloro-2-(2,6-difluorophenylmethyl)-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide, a new anti-HIV-1 agent targeted to reverse transcriptase, into the more active (S)-enantiomer is described. The method utilizes repetition of the following two steps: 1) semipreparative enantioseparation by HPLC on chiral stationary phase; 2) base-induced racemization of the less active (R)-enantiomer.

High-performance liquid chromatography (HPLC) was used for the enantiomeric separation of chiral imidazole derivatives endowed with antimycotic activity. Enantioselective columns, containing carbamates of cellulose and amylose, were used. The influence of the nature and content of an alcoholic modifier in the mobile phase was studied. The isolated enantiomers, separated on semipreparative columns, were submitted to in vitro biological investigations.

Various cinnammoyl-based structures were synthesized and tested in enzyme assays as inhibitors of the HIV-1 integrase (IN). The majority of compounds were designed as geometrically or conformationally constrained analogues of caffeic acid phenethyl ester (CAPE) and were characterized by a syn disposition of the carbonyl group with respect to the vinylic double bond. Since the cinnamoyl moiety present in flavones such as quercetin (inactive on HIV-1-infected cells) is frozen in an anti arrangement, it was hoped that fixing our compounds in a syn disposition could favor anti-HIV-1 activity in cell-based assays. Geometrical and conformational properties of the designed compounds were taken into account through analysis of X-ray structures available from the Cambridge Structural Database. The polyhydroxylated analogues were prepared by reacting 3,4-bis(tetrahydropyran-2-yloxy)benzaldehyde with various compounds having active methylene groups such as 2-propanone, cyclopentanone, cyclohexanone, 1,3-diacetylbenzene, 2, 4-dihydroxyacetophenone, 2,3-dihydro-1-indanone, 2,3-dihydro-1, 3-indandione, and others. While active against both 3'-processing and strand-transfer reactions, the new compounds, curcumin included, failed to inhibit the HIV-1 multiplication in acutely infected MT-4 cells. Nevertheless, they specifically inhibited the enzymatic reactions associated with IN, being totally inactive against other viral (HIV-1 reverse transcriptase) and cellular (RNA polymerase II) nucleic acid-processing enzymes. On the other hand, title compounds were endowed with remarkable antiproliferative activity, whose potency correlated neither with the presence of catechols (possible source of reactive quinones) nor with inhibition of topoisomerases. The SARs developed for our compounds led to novel findings concerning the molecular determinants of IN inhibitory activity within the class of cinnamoyl-based structures. We hypothesize that these compounds bind to IN featuring the cinnamoyl residue C=C-C=O in a syn disposition, differently from flavone derivatives characterized by an anti arrangement about the same fragment. Certain inhibitors, lacking one of the two pharmacophoric catechol hydroxyls, retain moderate potency thanks to nonpharmacophoric fragments (i.e., a m-methoxy group in curcumin) which favorably interact with an "accessory" region of IN. This region is supposed to be located adjacent to the binding site accommodating the pharmacophoric dihydroxycinnamoyl moiety. Disruption of coplanarity in the inhibitor structure abolishes activity owing to poor shape complementarity with the target or an exceedingly high strain energy of the coplanar conformation.

Summary Reaction of arylacetyl chlorides on thiophene or pyrrole derivatives furnished 2-aryl-1-(2-thienyl)- or 2-aryl-1-(1 H -pyrrol-2-yl)-1-ethanones. Reduction of ketones to the corresponding carbinols and reaction of the latter compounds with 1,1′-sulfonyldiimidazole or 1,1′-carbonyldiimidazole gave 2-thienyl- and 1 H -pyrrol-2-yl-1-aryl-2-( 1 H -imidazol-1-yl)ethanes, respectively. The new compounds were tested in vitro against a variety of pathogenic fungi in comparison with miconazole and bifonazole. Some 5-chloro-2-thienyl derivatives were endowed with good antifungal activity, particularly against Candida albicans and Cryptococcus neoformans .

Synthesis of 2-phenyl and 2,3-diphenylpyrroles bearing at the 4 position electronwithdrawing groups by reaction of tosylbenzylisocyanide (TosBIC) with various Michael acceptors was investigated. Sodium hydride and n-butyllithium were used as deprotonating agents for the synthesis of monophenyl and diphenylpyrroles, respectively.

Summary The synthesis of some N-[2-(1H-pyrrol-1-yl)benzyl]arylacetamides and new 4-arylmethyl-5,6-dihydro-4H-pyrrolo[1,2-a]-[1,4]benzodiazepines as their conformationally restricted analogues is reported. The reduction of arylacetamides and N-methylation of pyrrolobenzodiazepines led to the corresponding N-[2-(lH-pyrrol-1-yl)benzyl]arylethylamines and the 4-arylmethyl-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines, respectively. The new compounds were subjected to pharmacological tests for evaluation of antinociceptive effects. Neurobehavioural assays were also carried out on selected compounds to acquire data on neurotoxicity. Among the derivatives tested, arylacetamides 7b and 7e and 4-(4-methoxybenzyl)-5-methyl-5,6-dihydro-4H-pyrrolo[l,2-a][1,4]benzodiazepine 10d were the most active derivatives in antinociceptive assays, showing high significance in both hot-plate and acetic-acid-induced writhing tests in mice without sedative or myorelaxant effects.

Summary Reaction of arylacetyl chlorides on thiophene or pyrrole derivatives furnished 2-aryl-1-(2-thienyl)- or 2-aryl-1-(1 H -pyrrol-2-yl)-1-ethanones. Reduction of ketones to the corresponding carbinols and reaction of the latter compounds with 1,1′-sulfonyldiimidazole or 1,1′-carbonyldiimidazole gave 2-thienyl- and 1 H -pyrrol-2-yl-1-aryl-2-( 1 H -imidazol-1-yl)ethanes, respectively. The new compounds were tested in vitro against a variety of pathogenic fungi in comparison with miconazole and bifonazole. Some 5-chloro-2-thienyl derivatives were endowed with good antifungal activity, particularly against Candida albicans and Cryptococcus neoformans .

Ethyl 3-(arylthio)acrylates did not react with α-alkali metalated tosylmethyl isocyanide (TosMIC) to afford 4-(arylthio)pyrrole-3-carboxylic acid ethyl esters. Oxidation of thioethers to sulfones generated reactive 3-(arylsulfonyl) acrylates, which promptly underwent cycloaddition with TosMIC in the presence of base giving ethyl 4-(arylsulfonyl)pyrrole-3-carboxylates. Contrary to expectation, the use of ethyl 3-(5-chloro-2-nitrophenylsulfonyl)acrylate led to ethyl ester of 5-tosylpyrrole-3-carboxylic acid instead of the expected ethyl 4-(5-chloro-2-nitrophenylsulfonyl)pyrrole-3-carboxylate.

Optically active synthetic and semisynthetic polymers were utilized as chiral stationary phases (CSPs) for the direct chromatographic enantioseparation of a series of 8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one and thione 1,1-dioxide. Evaluation of stereochemical integrity of chiral analytes was assessed by enantioselective temperature and flow-dependent HPLC. A stopped-flow high-performance liquid chromatography (sfHPLC) procedure was developed for the determination of the rate constants and free energy barriers of enantiomerization of enantiomers of 8-chloro-2-(3-methyl-but-2-enyl)-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-thione 1,1-dioxide (compound 2) in the presence of Chiraspher and Chiralcel OD CSPs. In order to study the chiroptical properties of the individual enantiomers of analytes investigated, semipreparative chromatographic resolutions were performed. The assignment of the absolute configuration was empirically established by comparing the CD spectra of the separated enantiomers with those obtained from structural analogues.

The synthesis of pyrrolo[2,1-d][1,2,5]benzothiadiazepin-7(6H)-one 5,5-dioxide has been achieved by reaction between 2-(1H-pyrrol-1-yl)benzenesulfonamide and triphosgene. N-Ethylation of the tricyclic derivative afforded 6-ethylpyrrolo[2,1-d][1,2,5] benzothiadiazepin-7(6H)-one 5,5-dioxide, also obtained by the action of trifosgene on N-ethyl 2-(1H-pyrrol-1-yl)benzenesulfonamide. Preparation of pyrrole derivatives from 2-aminobenzenesulfonamide and its N-ethyl derivative by Clauson-Kaas procedure required preliminary protection of the sulfonamide function.

A series of 56 azole antifungal agents belonging to chemically diverse families related to bifonazole, one of the antimycotic drugs of clinical use, were investigated using the comparative molecular field analysis (CoMFA) paradigm. The studied compounds, which have been already synthesized and reported to be active in vitro against Candida albicans, were divided into a training set and a test set. The training set consisted of 40 molecules from all the different structural classes. Due to the lack of experimental structural data on these derivatives, molecular mechanics techniques were used to obtain putative active conformations for all the compounds. the correctness of this molecular modeling work was confirmed a posteriori by comparison with structural data of the analog 2w obtained by X-ray crystallographic analysis (Massa, S.; et al. Eur. J. Med. Chem. 1992, 27, 495-502). Two different alignment rules of the training set molecules were used in this study and are based on the assumption that according to published results on azole antifungal agents, all the studied compounds exert their inhibitory activity through the coordination of their azole moiety to the protoporphyrin iron atom of the fungal lanosterol 14alpha-demethylase enzyme. The predictive ability of each resultant CoMFA model was evaluated using a test set consisting of 16 representative compounds that belong to all the different structural classes. The best 3D-quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.57, 0.95, and 0.69, respectively. The average absolute error of predictions of this model is 0.30 log units, and the structural moieties of the studied antifungal agents which are thought to contribute to the biological activity were identified. The predictive capability of this model could be exploited in further synthetic studies on antifungal azoles. Furthermore, the results obtained by using two different alignments of the inhibitors suggest that the binding mode of these molecules involves both a coordination to the iron protoporphyrin atom and an additional, likewise relevant, hydrophobic interaction with the active site.

Summary The synthesis of some N-[2-(1H-pyrrol-1-yl)benzyl]arylacetamides and new 4-arylmethyl-5,6-dihydro-4H-pyrrolo[1,2-a]-[1,4]benzodiazepines as their conformationally restricted analogues is reported. The reduction of arylacetamides and N-methylation of pyrrolobenzodiazepines led to the corresponding N-[2-(lH-pyrrol-1-yl)benzyl]arylethylamines and the 4-arylmethyl-5-methyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,4]benzodiazepines, respectively. The new compounds were subjected to pharmacological tests for evaluation of antinociceptive effects. Neurobehavioural assays were also carried out on selected compounds to acquire data on neurotoxicity. Among the derivatives tested, arylacetamides 7b and 7e and 4-(4-methoxybenzyl)-5-methyl-5,6-dihydro-4H-pyrrolo[l,2-a][1,4]benzodiazepine 10d were the most active derivatives in antinociceptive assays, showing high significance in both hot-plate and acetic-acid-induced writhing tests in mice without sedative or myorelaxant effects.

Various bipyrryl analogues of bifonazole were synthesized starting from aryl-3-pyrryl-1-imidazolylmethanes. The introduction of a second pyrryl portion was performed by linking an acrylate moiety at 1-position of the pyrrole ring and then by treatment with TosMIC. The bipyrryl esters were hydrolyzed and decarboxylated to afford the required imidazoles. All new imidazole derivatives were tested against Candida albicans and Candida spp using as standard controls miconazole, bifonazole and ketoconazole.

Various derivatives of 1,2-diaryl-1-(1H-imidazol-1-yl)ethane have been synthesized and tested against Candida albicans and Candida spp. In vitro essays showed chloro and amino derivatives to be as active as miconazole and bifonazole and more potent than ketoconazole. Structure-activity relationships of the new imidazole antifungal agents are discussed.

The synthesis of some 2-aryl-1-(4-methoxyphenyl)-1-(1 H -imidazol-1-yl)ethane derivatives and related 1 H -1,2,4- and 1 H -1,3,4-triazoles is described. The molecular structure of new derivatives has been established by 1H NMR spectra and X-ray crystallographic analysis. When tested in solid agar cultures the azole derivatives showed from moderate to potent in vitro antifungal activity against Candida albicans and Candida spp.

The competition between rearrangement of the excited allyl radical via a 1,3 sigmatropic shift versus sequential 1,2 shifts has been observed and characterized using isotopic substitution, laser excitation, and molecular beam techniques. Both rearrangements produce a 1-propenyl radical that subsequently dissociates to methyl plus acetylene. The 1,3 shift and 1,2 shift mechanisms are equally probable for CH(2)CHCH(2), whereas the 1,3 shift is favored by a factor of 1.6 in CH(2)CDCH(2). The translational energy distributions for the methyl and acetylene products of these two mechanisms are substantially different. Both of these allyl dissociation channels are minor pathways compared to hydrogen atom loss.

Bromination of 1-(1-methyl-1H-pyrro]-2-yl)-2-phenylethanone with 1 mole of copper-(II) bromide in chloroform-ethyl acetate 1:1 mixture results in the regiospecific formation of 2-bromo-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethanone. Similar reaction with 1 mole of N-bromosuccinimide leads to α- and β-monosubstitution at pyrrole ring without affect the methylene group.

Serum erythromycin concentration data from several repetitive dosing studies were analyzed with newly developed computer methods for fitting multiple-dose data and generating nonlinear least-squares estimates of pharmacokinetic parameters. This analysis indicates that the pharmacokinetics of erythromycin can be described by a one-compartment linear model with the following characteristics: (a) a lag time between the time of drug administration and the onset of absorption; (b) apparent zero-order rather than first-order absorption; (c) dose-to-dose variability in the rate and extent of absorption; and (d) day-to-day variability in the kinetics of elimination. The bioavailability of the third dose of erythromycin on a given day is considerably lower than that of the second dose or of the fourth and last dose of the day. The average apparent half-life of erythromycin was 1.8 hour on day 1 and 2.6 hours on day 3 of the repetitive dosing regimen.

Bromination of 1-(1-methyl-1H-pyrro]-2-yl)-2-phenylethanone with 1 mole of copper-(II) bromide in chloroform-ethyl acetate 1:1 mixture results in the regiospecific formation of 2-bromo-1-(1-methyl-1H-pyrrol-2-yl)-2-phenylethanone. Similar reaction with 1 mole of N-bromosuccinimide leads to α- and β-monosubstitution at pyrrole ring without affect the methylene group.

The case statement is the primary document upon which an organization bases its appeal for financial and philosophical support. This author points out how a well-constructed case statement can impact on fund raising success.