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The development of multifunctional catalysts is a necessary step to effectively carry out one-pot cascade reactions, such as that from furfural to γ-valerolactone. This research effort faces the challenge posed by the intrinsic limit of how many kinds of catalytic sites a single material can bear. In this work, the application of Spray-Freeze Drying (SFD) as a synthetic technique for the preparation of a wide range of innovative composite multi-functional catalysts is reported. Herein we show that by the proper combination of Aquivion as a highly active Brønsted acid catalyst and metal oxides as both support materials and Lewis acids (LAS) enable to achieve highly unique efficient and effective dual acid composite catalysts that are able to carry out the cascade reaction from furfural to γ-valerolactone. The dual catalytic system comprised of Aq/ZrO2 with 30 % polymer content prepared via spray-freeze drying exhibited GVL yields of 25 % after only 2 h at 180 °C and a remarkably high productivity of 4470 µmolGVL gCat -1 h-1, one of the highest reported results. Mechanistic studies based on experimental and advanced characterisation and spectroscopic techniques, such as, SEM, TEM, 15N MAS NMR and 19F MAS NMR indicate that activity arises from the proper tuning of BAS/LAS (Brønsted Acid Site/Lewis Acid Site) acidic properties.

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In recent years, halogen-bonded complexes (XBCs), in solution, have played a pivotal role in inducing photochemical organic reactions. In this work, we explore the ability of various tertiary amines to act as XB acceptors in the presence of the XB donor CBr4 by computational and spectroscopic studies. DFT studies clearly showcase the formation of XBCs between the studied tertiary amines and CBr4. Simultaneously, computational and experimental UV-Vis studies display intense red shifts that are consistent with charge transfer observed from tertiary amines to CBr4. A detailed NMR study revealed a clear chemical shift of the carbon carrying the bromine atoms upon mixing the XB acceptor with the donor, suggesting that this spectroscopic technique is indeed an experimental tool to identify the generation of XBCs. An application of the ability of such XBCs to activate a carboxylic acid under UVA irradiation or sunlight is presented for amino acid coupling. Among the various tertiary amines studied, the pair DABCO-CBr4 was found to work well for the photochemical amide bond formation. Direct infusion-HRMS studies allowed us to propose a general mechanism for the photochemical amino acid coupling in the presence of a tertiary amine and CBr4, initiated by the photoactivation of an XBC.

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Natural products obtained from marine organisms continue to be a rich source of novel structural architecture and of importance in drug discovery, medicine, and health. However, the success of such endeavors depends on the exact structural elucidation and access to sufficient material, often by stereoselective total synthesis, of the isolated natural product of interest. (-)-Mucosin (1), a fatty acid derivative, previously presumed to contain a rare cis-bicyclo[4.3.0]non-3-ene moiety, has since been shown to be the trans-congener. Analytically, the fused bicyclic ring system in (-)-1 constitutes a particular challenge in order to establish its relative and absolute stereochemistry. Herein, data from biological evaluations, NMR and molecular modeling studies of (-)-1 are presented. An overview of the synthetic strategies enabling the exact structural elucidation of (-)-mucosin (1) is also presented.

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The coordination chemistry of 2-pyridyl ketoximes continues to attract the interest of many inorganic chemistry groups around the world for a variety of reasons. Cadmium(II) complexes of such ligands have provided models of solvent extraction of this toxic metal ion from aqueous environments using 2-pyridyl ketoxime extractants. Di-2-pyridyl ketone oxime (dpkoxH) is a unique member of this family of ligands because its substituent on the oxime carbon bears another potential donor site, i.e., a second 2-pyridyl group. The goal of this study was to investigate the reactions of cadmium(II) halides and dpkoxH in order to assess the structural role (if any) of the halogeno ligand and compare the products with their zinc(II) analogs. The synthetic studies provided access to complexes {[CdCl2(dpkoxH)∙2H2O]}n (1∙2H2O), {[CdBr2(dpkoxH)]}n (2) and {[CdI2(dpkoxH)]}n (3) in 50-60% yields. The structures of the complexes were determined by single-crystal X-ray crystallography. The compounds consist of structurally similar 1D zigzag chains, but only 2 and 3 are strictly isomorphous. Neighboring CdII atoms are alternately doubly bridged by halogeno and dpkoxH ligands, the latter adopting the η1:η1:η1:µ (or 2.0111 using Harris notation) coordination mode. A terminal halogeno group completes distorted octahedral coordination at each metal ion, and the coordination sphere of the CdII atoms is {CdII(η1 - X)(µ - X)2(Npyridyl)2(Noxime)} (X = Cl, Br, I). The trans-donor-atom pairs in 1∙2H2O are Clterminal/Noxime and two Clbridging/Npyridyl; on the contrary, these donor-atom pairs are Xterminal/Npyridyl, Xbridging/Noxime, and Xbridging/Npyridyl (X = Br, I). There are intrachain H-bonding interactions in the structures. The packing of the chains in 1∙2H2O is achieved via π-π stacking interactions, while the 3D architecture of the isomorphous 2 and 3 is built via C-H∙∙∙Cg (Cg is the centroid of one pyridyl ring) and π-π overlaps. The molecular structures of 1∙2H2O and 2 are different compared with their [ZnX2(dpkoxH)] (X = Cl, Br) analogs. The polymeric compounds were characterized by IR and Raman spectroscopies in the solid state, and the data were interpreted in terms of the known molecular structures. The solid-state structures of the complexes are not retained in DMSO, as proven via NMR (1H, 13C, and 113Cd NMR) spectroscopy and molar conductivity data. The complexes completely release the coordinated dpkoxH molecule, and the dominant species in solution seem to be [Cd(DMSO)6]2+ in the case of the chloro and bromo complexes and [CdI2(DMSO)4].

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Cystobactamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such aromatic oligoamides were proposed to inhibit α-helix-mediated protein-protein interactions and may serve for specific recognition of DNA. Based on this suggestion, we designed new derivatives that have duplicated cystobactamid triarene units as model systems to decipher the specific binding mode of cystobactamids to double stranded DNA. Solution NMR analyses revealed that natural cystobactamids as well as their elongated analogues show an overall bent shape at their central aliphatic unit, with an average CX-CY-CZ angle of ~110 degrees. Our finding is corroborated by the target-bound structure of close analogues, as established by cryo-EM very recently. Cystobactamid CN-861-2 binds directly to the bacterial gyrase with an affinity of 9 µM, and also exhibits DNA-binding properties with specificity for AT-rich DNA. Elongation/dimerization of the triarene subunit of native cystobactamids is demonstrated to lead to an increase in DNA binding affinity. This implies that cystobactamids' gyrase inhibitory activity necessitates not just interaction with the gyrase itself, but also with DNA via their triarene unit.

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Abiraterone acetate (AbirAc) is the most used steroidal therapeutic agent for treatment of prostate cancer. The mainly hydrophobic molecular surface of AbirAc results in its poor solubility and plays an important role for retention of abiraterone in the cavity of the receptor formed by peptide chains and heme fragments. In order to evaluate the hydrolytic stability of AbirAc, to modify its solubility by formation of new solid forms and to model bonding of this medication with the heme, a series of d-metal complexes with AbirAc was obtained. AbirAc remains stable in water, acetonitrile, tetrahydrofuran, and ethanol, and readily interacts with dications as a terminal ligand to create discrete complexes, including [FePC(AbirAc)2] and [ZnTPP(AbirAc)] (H2PC = phthalocyanine and H2TPP = 5,10,15,20-tetraphenylporphyrine) models for ligand-receptor bonding. In reactions with silver(I) nitrate, AbirAc acts as a bridge ligand. Energies of chemical bonding between AbirAc and these cations vary from 97 to 235 kJ mol-1 and exceed those between metal atoms and water molecules. This can be indicative of the ability of abiraterone to replace solvent molecules in the coordination sphere of biometals in living cells, although the model [ZnTPP] complex remains stable in CDCl3, CD2Cl2, and 1,1,2,2-tetrachloroethane-d2 solvents and decomposes in polar dimethylsulfoxide-d6 and methanol-d4 solvents, as follows from the 1H DOSY spectra. Dynamics of its behavior in 1,1,2,2-tetrachloroethane-d2 were studied by ROESY and NMR spectra.

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Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-ß-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer's Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon H2O2 exposure, as a general source of ROS.

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A pure water soluble xylan (PS-I) with an average molecular weight ~1.1 × 105 Da was isolated from the hot water extraction of fresh leaves of Piper betle (paan). The xylan was found to be composed of xylose, galactose and methyl galacturonate in a molar ratio of nearly 3:1:1. The repeating unit was composed of a backbone containing three (1 â†’ 4)-α-D-Xylp residues, one of which was branched at O-2 position with the side chain consisting of (1 â†’ 4)-α-D-GalpA6Me and terminal ß-D-Galp residues. This xylan exhibited macrophage, splenocyte, and thymocyte stimulatory activities. In vitro antioxidant studies demonstrated that the xylan has DPPH radical scavenging potential (EC50 = 148 µg/mL), ABTS radical quenching activity (EC50 = 188 µg/mL) and ferrous ions chelating activity (EC50 = 370 µg/mL). These findings elicit the need for further exploration of the xylan as a natural antioxidant and a potent immunostimulating agent.

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Fluorescent receptors (4a-4c) based on (thio)ureido-functionalized hexahomotrioxacalix[3]arenes were synthesised and obtained in the partial cone conformation in solution. Naphthyl or pyrenyl fluorogenic units were introduced at the lower rim of the calixarene skeleton via a butyl spacer. The binding of biologically and environmentally relevant anions was studied with NMR, UV-vis absorption, and fluorescence titrations. Fluorescence of the pyrenyl receptor 4c displays both monomer and excimer fluorescence. The thermodynamics of complexation was determined in acetonitrile and was entropy-driven. Computational studies were also performed to bring further insight into the binding process. The data showed that association constants increase with the anion basicity, and AcO-, BzO- and F- were the best bound anions for all receptors. Pyrenylurea 4c is a slightly better receptor than naphthylurea 4a, and both are more efficient than naphthyl thiourea 4b. In addition, ureas 4a and 4c were also tested as ditopic receptors in the recognition of alkylammonium salts.

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The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2 + domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

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Hexacoordinated heteroligand silicon catecholates, although being prospective as easily soluble compounds with high hydrolytic stability and diverse redox properties, have been insufficiently studied. The transesterification of 1-(trimethoxysilylmethyl)-2-oxohexahydroaze or N-methyl-N-(trimethoxysilylmethyl)acetamide by two equivalents of catechol derivatives in the presence of dicyclohexylamine afforded a series of target compounds in good yield. The complexes were characterized using elemental analysis, FTIR, 1H, 13C and 29Si NMR spectra, X-ray crystallography and cyclic voltammetry. X-ray diffraction confirmed that the silicon atom possesses the octahedral geometry of the SiCO5 polyhedron that remains unchanged in solution as it follows from 29Si NMR data. The compounds demonstrated up to three oxidation waves; and the reduction profile strongly depended on the nature of the substituents on a catecholate anion.

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In the title compound, [Al2Br4(CH2)(C4H10O)2], the mol-ecule lies on a crystallographic twofold axis passing through the bridging C atom. Each AlIII atom is four-coordinate, being bonded to two bromide ions, bridging the CH2 group as well as the oxygen atom of a diethyl ether ligand in a slightly distorted tetra-hedral arrangement with angles ranging from 101.52 (8) to 116.44 (5)°. The Al-CH2-Al angle, 118.4 (2)°, is the smallest observed for a structure where this moiety is not part of a ring. In the crystal, weak C-H⋯Br inter-actions, characterized as R 2 2(12) rings, link the mol-ecules into ribbons in the [101] direction. The title compound is monomeric and coordinatively saturated in the solid state, as each aluminum is four-coordinate, but in solution the ether mol-ecules from either or both Al atoms can dissociate, and would be expected to rapidly exchange, and this is supported by NMR data.

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Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme.

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The two isotopomers of teriflunomide were synthesized starting from isotopically stable-labeled stocks of [13 C]potassium cyanide and [1-13 C]ethyl bromoacetate. The two 13 C-labeled compounds 1a, b were applied in several NMR studies to study the E/Z ratio in different matrices. In a solution, such as dimethyl sulfoxide (DMSO), a dynamic equilibrium between E/Z-isomers (ratio of 8:92) was determined by initial 13 C-carbon NMR experiments. To get insights into the E/Z ratio of teriflunomide under in vivo conditions, advanced heteronuclear NMR (heteronuclear Overhauser effect spectroscopy [HOESY]) in D2 O and mixtures of D2 O/plasma were performed. Whereas NMR experiments in mixtures of water and plasma failed owing to extreme line broadening, NMR spectra in water at pH 7.4 showed only the Z-isomer.

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A water soluble polysaccharide (PGPS) with molecular weight ~ 1.4 × 105 Da was isolated by alkali treatment from an edible mushroom Polyporus grammocephalus and purified by gel chromatography using sepharose-6B column. Monosaccharide analysis revealed that PGPS was made up of glucose only. PGPS contained (1 â†’ 3)-α-D-Glcp and (1 â†’ 4)-α-D-Glcp moieties in a molar ratio of nearly 1:2. Through a series of chemical and spectroscopic (1D/2D NMR) investigations, the repeating unit of the glucan was established as: →3)-α-D-Glcp(1 â†’ [4)-α-D-Glcp(1]2→ This α-glucan was observed to stimulate some prime components of immune system, namely, macrophages, splenocytes, and thymocytes.

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This study aimed to investigate the molecular characterization, antioxidant activity in vitro, cytotoxicity study of an exopolysaccharide isolated from Citrobacter freundii. Firstly, the culture conditions were standardized by the Design of experiments (DoE) based approach, and the final yield of thecrude exopolysaccharide was optimized at 2568 ± 169 mg L-1. One large fraction of exopolysaccharide was obtained from the culture filtrate by size exclusion chromatography and molecular characteristics were studied. A new mannose rich exopolysaccharide (Fraction-I) with average molecular weight ~ 1.34 × 105 Da was isolated. The sugar analysis showed the presence of mannose and glucose in a molar ratio of nearly 7:2 respectively. The structure of the repeating unit in the exopolysaccharide was determined through chemical and 1D/2D- NMR experiments as: Finally, the antioxidant activity, and the cytotoxicity of the exopolysaccharide were investigated and the relationship with molecular properties was discussed as well.

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The present study provides new evidence that cationic porphyrins may be considered as tunable platforms to interfere with the structural "key code" present on the 20S proteasome α-rings and, by consequence, with its catalytic activity. Here, we describe the functional and conformational effects on the 20S proteasome induced by the cooperative binding of the tri-cationic 5-(phenyl)-10,15,20-(tri N-methyl-4-pyridyl) porphyrin (Tris-T4). Our integrated kinetic, NMR, and in silico analysis allowed us to disclose a complex effect on the 20S catalytic activity depending on substrate/porphyrin concentration. The analysis of the kinetic data shows that Tris-T4 shifts the relative populations of the multiple interconverting 20S proteasome conformations leading to an increase in substrate hydrolysis by an allosteric pathway. Based on our Tris-T4/h20S interaction model, Tris-T4 is able to affect gating dynamics and substrate hydrolysis by binding to an array of negatively charged and hydrophobic residues present on the protein surface involved in the 20S molecular activation by the regulatory proteins (RPs). Accordingly, despite the fact that Tris-T4 also binds to the α3ΔN mutant, allosteric modulation is not observed since the molecular mechanism connecting gate dynamics with substrate hydrolysis is impaired. We envisage that the dynamic view of the 20S conformational equilibria, activated through cooperative Tris-T4 binding, may work as a simplified model for a better understanding of the intricate network of 20S conformational/functional states that may be mobilized by exogenous ligands, paving the way for the development of a new generation of proteasome allosteric modulators.

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Fluorescent dihomooxacalix[4]arene-based receptors 5a-5c, bearing two naphthyl(thio)ureido groups at the lower rim via a butyl spacer, were synthesised and obtained in the cone conformation in solution. The X-ray crystal structures of 1,3- (5a) and 3,4-dinaphthylurea (5b) derivatives are reported. Their binding properties towards several anions of different geometries were assessed by 1H-NMR, UV-Vis absorption and fluorescence titrations. Structural and energetic insights of the naphthylurea 5a and 5b complexes were also obtained using quantum mechanical calculations. The data showed that all receptors follow the same trend, the association constants increase with the anion basicity, and the strongest complexes were obtained with F-, followed by the oxoanions AcO- and BzO-. Proximal urea 5b is a better anion receptor compared to distal urea 5a, and both are more efficient than thiourea 5c. Compounds 5a and 5b were also investigated as heteroditopic receptors for biologically relevant alkylammonium salts, such as the neurotransmitter γ-aminobutyric acid (GABA·HCl) and the betaine deoxycarnitine·HCl. Chiral recognition towards the guest sec-butylamine·HCl was also tested, and a 5:2 selectivity for (R)-sec-BuNH3+·Cl- towards (P) or (M) enantiomers of the inherently chiral receptor 5a was shown. Based on DFT calculations, the complex [(S)-sec-BuNH3+·Cl-/(M)-5a] was indicated as the more stable.

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A water soluble heteroglycan (THPS) of an average molecular weight ~1.98 × 105 Da was isolated from the aqueous extract of the fruit bodies of an edible mushroom Termitomyces heimii. Structural characterization of THPS was carried out using acid hydrolysis, methylation analysis, periodate oxidation, Smith degradation and 1D/2D NMR studies. Sugar analysis indicated the presence of glucose, mannose, galactose, and fucose in a molar ratio of nearly 6:2:2:1. The repeating unit of the THPS had a backbone consisting of four (1 â†’ 3)-ß-d-glucopyranosyl, one (1 â†’ 6)-ß-d-glucopyranosyl, two (1 â†’ 3)-α-D-manopyranosyl, and two (1 â†’ 6)-α-D-galactopyranosyl residues, out of which one (1 â†’ 3)-ß-d-glucopyranosyl residue was branched at O-6 position with terminal ß-d-glucopyranosyl residue and one (1 â†’ 6)-α-D-galactopyranosyl residue was branched at O-2 position with terminal α-L-fucopyranosyl residue.

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The Mur ligases form a series of consecutive enzymes that participate in the intracellular steps of bacterial peptidoglycan biosynthesis. They therefore represent interesting targets for antibacterial drug discovery. MurC, D, E and F are all ATP-dependent ligases. Accordingly, with the aim being to find multiple inhibitors of these enzymes, we screened a collection of ATP-competitive kinase inhibitors, on Escherichia coli MurC, D and F, and identified five promising scaffolds that inhibited at least two of these ligases. Compounds 1, 2, 4 and 5 are multiple inhibitors of the whole MurC to MurF cascade that act in the micromolar range (IC50, 32-368 µM). NMR-assisted binding studies and steady-state kinetics studies performed on aza-stilbene derivative 1 showed, surprisingly, that it acts as a competitive inhibitor of MurD activity towards D-glutamic acid, and additionally, that its binding to the D-glutamic acid binding site is independent of the enzyme closure promoted by ATP.

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