Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized imidazo pyranotacrines as non-hepatotoxic, multipotent tacrine analogues. Among these compounds, 1-(5-amino-2-methyl-4-(1-methyl-1H-imidazol-2-yl)-6,7,8,9-tetrahydro-4Hpyrano[2,3-b]quinolin-3-yl)ethan-1-one (4) is non-hepatotoxic (cell viability assay on HepG2 cells), a selective but moderately potent EeAChE inhibitor (IC 50 = 38.7 ± 1.7 μM), and a very potent antioxidant agent on the basis of the ORAC test (2.31 ± 0.29 μmol〈Trolox/μmol compound). © 2016 by the authors.

The presence of an unsaturation in a pyranose derivative provides a powerful handle for the creation of new compounds displaying a variety of molecular skeletons. This contribution focuses on investigations related to the use of pyranose glycals in the creation of skeletally-diverse derivatives that have appeared in the literature during the last eight years. © The Royal Society of Chemistry 2016.

Novel multifunctional tacrines for Alzheimer's disease were obtained by Ugi-reaction between ferulic (or lipoic acid), a melatonin-like isocyanide, formaldehyde, and tacrine derivatives, according to the antioxidant additive approach in order to modulate the oxidative stress as therapeutic strategy. Compound 5c has been identified as a promising permeable agent showing excellent antioxidant properties, strong cholinesterase inhibitory activity, less hepatotoxicity than tacrine, and the best neuroprotective capacity, being able to significantly activate the Nrf2 transcriptional pathway. © 2016 American Chemical Society.

Avarol is a marine sesquiterpenoid hydroquinone, previously isolated from the marine sponge Dysidea avara Schmidt (Dictyoceratida), with antiinflammatory, antitumor, antioxidant, antiplatelet, anti-HIV, and antipsoriatic effects. Recent findings indicate that some thio-avarol derivatives exhibit acetylcholinesterase (AChE) inhibitory activity. The multiple pharmacological properties of avarol, thio-avarol and/or their derivatives prompted us to continue the in vitro screening, focusing on their AChE inhibitory and neuroprotective effects. Due to the complex nature of Alzheimer's disease (AD), there is a renewed search for new, non hepatotoxic anticholinesterasic compounds. This paper describes the synthesis and in vitro biological evaluation of avarol-3′-thiosalicylate (TAVA) and thiosalycil-prenyl-hydroquinones (TPHs), as non hepatotoxic anticholinesterasic agents, showing a good neuroprotective effect on the decreased viability of SHSY5Y human neuroblastoma cells induced by oligomycin A/rotenone and okadaic acid. A molecular modeling study was also undertaken on the most promising molecules within the series to elucidate their AChE binding modes and in particular the role played by the carboxylate group in enzyme inhibition. Among them, TPH4, bearing a geranylgeraniol substituent, is the most significant Electrophorus electricus AChE (EeAChE) inhibitor (IC50 = 6.77 ± 0.24 μM), also endowed with a moderate serum horse butyrylcholinesterase (eqBuChE) inhibitory activity, being also the least hepatotoxic and the best neuroprotective compound of the series. Thus, TPHs represents a new family of synthetic compounds, chemically related to the natural compound avarol, which has been discovered for the potential treatment of AD. Findings prove the relevance of TPHs as a new possible generation of competitive AChE inhibitors pointing out the importance of the salycilic substituents on the hydroquinone ring. Since these compounds do not belong to the class of alkaloids, which are notorious for their capability to inhibit AChE while exhibiting side effects, they may constitute novel active AChE inhibitors with fewer side effects. © 2016 Elsevier Masson SAS

Herein we describe the synthesis and in vitro biological evaluation of thirteen new, racemic, diversely functionalized 2-chloroquinolin-3-yl substituted PyranoTacrines (PTs) as multipotent tacrine analogues for Alzheimer's disease (AD) therapy. Among these compounds, 1-(5-amino-4-(2-chloro-7-methoxyquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano [2,3-b]quinolin-3-yl)éthanone (9) and ethyl 5-amino-4-(2-chloroquinolin-3-yl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrano[2,3-b]quinoline-3-carboxylate (4) were found to be non-neurotoxic agents in human neuroblastoma SHSY5Y cells. Compounds 9 (IC50 = 0.47 ± 0.13 μM) and 4 (IC50 = 0.48 ± 0.05 μM) are potent, mixed-type (9: Ki = 0.0142 ± 0.003 μM), and selective EeAChE inhibitors, binding at the both catalytic and peripheral anionic site of the enzyme. Compounds 9 and 4 are neuroprotective agents at low μM concentrations upon decreased viability of SHSY5Y cells induced by oxidative stress, and stimulators of GSK3β-dependent tau phosphorylation. In addition, molecules 9 and 4 effectively counteract Aβ-aggregation on exposure to Aβ1-40, as well as Aβ1-40 aggregation-dependent tau-oligomerization and phosphorylation in 396Ser, which could be ascribed to the anti-aggregating properties shown in vitro. Thus, a new family of tacrine analogues, whose potent AChEI activity is linked to both their Aβ-aggregating and tau-phosphorylation inhibitory capacities, has been discovered for the potential treatment of AD. © 2016 Elsevier Masson SAS. All rights reserved.

The gene xylB from Caulobacter crescentus has been cloned and expressed in Escherichia coli providing a high yield of xylose dehydrogenase (XylB) production and excellent purity (97\%). Purified recombinant XylB showed an absolute dependence on the cofactor NAD+ and a strong preference for D-xylose against other assayed mono and disaccharides. Additionally, XylB showed strong stability when stored as freeze-dried powder at least 250 days both at 4 °C and room temperature. In addition, more than 80\% of the initial activity of rehydrated freeze-dried enzyme remained after 150 days of incubation at 4 °C. Based on these characteristics, the capability of XylB in D-xylose detection and quantification was studied. The linearity of the method was maintained up to concentrations of D-xylose of 10 mg/dL and the calculated limits of detection (LoD) and quantification (LoQ) of xylose in buffer were 0.568 mg/dL and 1.89 mg/dL respectively. Thus, enzymatic detection was found to be an excellent method for quantification of D-xylose in both buffer and urine samples. This method can easily be incorporated in a new test for the diagnosis of hypolactasia through the measurement of intestinal lactase activity. © 2016 Elsevier B.V.

Currently available drugs against Alzheimer's disease (AD) are only able to ameliorate the disease symptoms resulting in a moderate improvement in memory and cognitive function without any efficacy in preventing and inhibiting the progression of the pathology. In an effort to obtain disease-modifying anti-Alzheimer's drugs (DMAADs) following the multifactorial nature of AD, we have recently developed multifunctional compounds. We herein describe the design, synthesis, molecular modeling and biological evaluation of a new series of donepezil-related compounds possessing metal chelating properties, and being capable of targeting different enzymatic systems related to AD (cholinesterases, ChEs, and monoamine oxidase A, MAO-A). Among this set of analogues compound 5f showed excellent ChEs inhibition potency and a selective MAO-A inhibition (vs MAO-B) coupled to strong complexing properties for zinc and copper ions, both known to be involved in the progression of AD. Moreover, 5f exhibited moderate antioxidant properties as found by in vitro assessment. This compound represents a novel donepezil–hydroxyquinoline hybrid with DMAAD profile paving the way to the development of a novel class of drugs potentially able to treat AD. © 2015 Elsevier Masson SAS

The present study provides insights into the manner in which the configuration of β-aminoallene precursors affects their gold-catalyzed cyclization reactions. The reactivity can be switched by using indolizidinone-tethered β-aminoallenes bearing the syn- or the anti-disposition of both protons at the α- and β-allenic stereocenters. Fused heterocycles (seven examples, 60-75\% yields) are obtained from the syn-precursors, while a dimerization-aminoketalization-spirocyclization sequence to afford benzo[b]pyrrolo[3,2,1-ij][1,7]naphthyridin-1-ones (four examples, 34-48\% yields) can be achieved starting from their anti-isomers. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Controlled preparation of 2,5-dihydro-1H-pyrroles, 3,6-dihydro-2H-pyrans, and pyrroles has been achieved through switchable chemo- and regioselectivity in the metal-catalyzed heterocyclization reactions of allenic amino alcohols. The gold-catalyzed cycloisomerization reaction of α-amino-β-hydroxyallenes was effective as 5-endo cyclization by addition of amino functionality to the distal allene carbon to yield enantiopure 2,5-dihydro-1H-pyrroles, whereas their palladium-catalyzed cyclizative coupling reactions furnished 3,6-dihydro-2H-pyrans through a chemo- and regioselective 6-endo cycloetherification. Conversely, the gold-catalyzed heterocyclization reaction of β-amino-γ-hydroxyallenes generated exclusively pyrrole derivatives. These results could be explained through a chemo- and regioselective 5-exo aminocyclization to the central allene carbon followed by aromatization. Chemo- and regioselectivity depend on both linker elongation as well as the type of catalyst. This behavior can be justified by means of density functional theory calculations. © 2016 American Chemical Society.

A new yellow-green emitting hyperbranched fluorescent sensor derived from 4-(N,N-dimethylaminoethylamine)-1,8-naphthalimide has been synthesized for the first time through click chemistry, and its properties have been compared to those of its low molecular weight reference compound. The reactive chromophore, bearing a triple bond, has been synthesized in high yield in a two-step procedure by microwave irradiation. Solvatochromic study of the hyperbranched probe in several solvents using ET30, π∗ and SPP scales demonstrates that there is not a loss of sensitivity towards polarity when the sensor moiety is included in the hyperbranched structure. The ability of the new compounds to detect cations was evaluated in solution by the increase in their fluorescence intensity in the presence of metal ions (Cu2+, Zn2+, Ni2+, Co2+, Cd2+, Fe3+, Ag+ and Hg2+) and protons. The hyperbranched sensor demonstrated the same sensitivity towards metal cations and protons than the reference chromophore, working through a photoinduced electron transfer mechanism typical of a fluorophore-spacer-receptor system. Experiments of long-term immersion of acrylic films doped with the probes showed no extraction of the hyperbranched fluorescent sensor, whereas the low molecular weight compound was continuously extracted from the film. © 2015 Elsevier Ltd.

We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line. © 2016 by the authors; licensee MDPI.

A method for the arylative coupling of alkynols or alkynyl hydroperoxides using equimolar amounts of diazonium salts at room temperature has been achieved through application of a gold/photoredox dual catalytic system. The excess of external reagents (oxidant or base) and high temperatures required by previous arylative Meyer-Schuster rearrangement protocols are avoided by exploitation of a visible light-mediated process. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A convenient ligand-free catalytic system has been developed for the chemoselective cyclization reaction of various α-allenol derivatives by palladium nanoparticles (PdNPs) in an aqueous reaction medium. (Figure presented.) . © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for α7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca2+ signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on α1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated. © 2016 American Chemical Society.

Bimetallic Zr(Ti)-NDC based metal-organic frameworks (MOFs) have been prepared by incorporation of titanium(iv) into zirconium(iv)-NDC-MOFs (UiO family). The resulting materials maintain thermal (up to 500 °C), chemical and structural stability with respect to parent Zr-MOFs as can be deduced from XRD, N2 adsorption, FTIR and thermal analysis. The materials have been studied in Lewis acid catalyzed reactions, such as, domino Meerwein-Ponndorf-Verley (MPV) reduction-etherification of p-methoxybenzaldehyde with butanol, isomerization of α-pinene oxide and cyclization of citronellal. © The Royal Society of Chemistry.

This work shows that a deprotection strategy of BODIPY conjugated porous polymers (CMPBDPs) can be successfully applied to synthesize a new (dipyrrin)(bipyridine)Ru(ii) (CMPBDP-Ru) efficient heterogeneous photocatalyst for iminium ion generation under visible light. CMPBDP-Ru shows high thermal and photochemical stability under irradiation, and it could be reused several times. © The Royal Society of Chemistry 2016.

A new and easy route to prepare “a la carte” bis(1,2,3-triazol-1-yl)methane compounds, namely bmtzm (1), bptzm (2), bttzm (3), bmtzpm (4), bptzpm (5), bttzpm (6), bmtzom (7), bptzom (8) and bttzom (9), with different functional groups is reported. The compounds were prepared by reaction between readily accessible alkynes and geminal diazides in a double Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These materials were used as starting materials for the synthesis of more elaborate compounds. Thus, the preparation of new bis(1,2,3-triazol-1-yl)methane-based heteroscorpionate neutral precursors pbptztamH (10), pbttztamH (11), (S)-mbptzamH (12) and (S)-mbttzamH (13) and a dinuclear zinc complex, [Zn{pbptztam}Et]2(14), was achieved. The structures of the compounds were determined by spectroscopic methods, and the X-ray crystal structures of compounds 2, 3, 7, 8, 9 and 14 were established. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

We report the synthesis, characterization and activity of new series of catalysts based on Niobium Mesoporous Cellular Foams (NbMCF), modified with alkaline metal elements. These materials exhibit very different acid-base properties attributed to the Nb source for the preparation of the catalysts and the presence and loading of different alkaline metals. The Me/NbMCF materials (where Me are alkaline metals) were tested in the reaction of 2-hydroxybenzaldehyde and ethyl cyanoacetate, under solvent-free conditions, at room temperature, leading to mixtures of the corresponding chromenes 4 and 5, as mixtures of diastereomers erythro/threo, in a 2:1 ratio, respectively, with good to excellent yields. Our experimental results indicate that the metal loading on the catalysts and the acid-base character, and the texture parameters are probably determining factors in the reactivity and the observed diastereoselectivity. The computational study suggests that the presence of alkaline oxides on Me/NbMCF catalyst, exhibiting strong basicity, activates the formation of the nucleophile species, the corresponding enolate, and initiates the reaction. However, the cation size has a deep impact on the stability of the reactant complex so that the effective aldolization could be obstructed by the presence of the bulkier centers. © 2016 Elsevier B.V.

[No abstract available]

Polycyclic aromatic hydrocarbons, and other semivolatile aromatic-like compounds, are an important and ubiquitous fraction of organic matter in the environment. The occurrence of semivolatile aromatic hydrocarbons is due to anthropogenic sources such as incomplete combustion of fossil fuels or oil spills, and other biogenic sources. However, their global transport, fate and relevance for the carbon cycle have been poorly assessed, especially in terms of fluxes. Here we report a global assessment of the occurrence and atmosphere-ocean fluxes of 64 polycyclic aromatic hydrocarbons analysed in paired atmospheric and seawater samples from the tropical and subtropical Atlantic, Pacific and Indian oceans. The global atmospheric input of polycyclic aromatic hydrocarbons to the global ocean is estimated at 0.09 Tg per month, four times greater than the input from the Deepwater Horizon spill. Moreover, the environmental concentrations of total semivolatile aromatic-like compounds were 10 2 -10 3 times higher than those of the targeted polycyclic aromatic hydrocarbons, with a relevant contribution of an aromatic unresolved complex mixture. These concentrations drive a large global deposition of carbon, estimated at 400 Tg C yr -1, around 15\% of the oceanic CO2 uptake. © 2016 Macmillan Publishers Limited.