A new biphenol-dipicolylamine based ligand and its dinuclear Zn2+ complex as fluorescent sensors for ibuprofen and ketoprofen in aqueous solution.

In this work, the study of the new ligand 3,3'-bis[N,N-bis(pyridine-2-ylmethyl)aminomethyl]-2,2'-dihydroxybiphenyl (L) is reported, where a central 2,2'-biphenol (BPH) fluorophore was functionalized at 3,3'-positions with two dipicolylamine (DPA) side arms as receptor units. Following the synthesis and full chemical-physical characterization, the acid-base and Zn2+-coordination abilities of L were investigated through a combination of potentiometric, UV-Vis, fluorescence, NMR, XRD and DFT measurements. The optical properties of the ligand turned out to be strongly dependent on the pH, being straightforwardly associated with the protonation state of the BPH moiety, whereas its peculiar design allowed to form stable mono and dinuclear Zn2+ complexes. In the latter species, the presence of two Zn2+ ions coordinatively unsaturated and placed at close distance to each other, prompted us to test their usefulness as metallo-receptors for two environmental pollutants of great relevance, ibuprofen and ketoprofen. Potentiometric and fluorescence investigations evidenced that these important non-steroidal anti-inflammatory drugs (NSAIDs) are effectively coordinated by the metallo-receptors and, of relevance, both the stability and the fluorescence properties of the resulting ternary adducts are markedly affected by the different chemical architectures of the two substrates. This study aims at highlighting the promising perspectives arising from the use of polyamino phenolic ligands as chemosensors for H+/Zn2+ and other additional anionic targets in their metal-complexed forms.

Ebselen analogues with dual human neutrophil elastase (HNE) inhibitory and antiradical activity.

Human neutrophil elastase (HNE) plays an essential role in host defense against bacteria but is also involved in several respiratory diseases. Recent reports suggest that compounds exhibiting a combination of HNE inhibitory activity with antiradical properties may be therapeutically beneficial for the treatment of respiratory diseases involving inflammation and oxidative stress. We report here the synthesis and biological evaluation of novel ebselen analogues exhibiting HNE inhibitory and antiradical activities. HNE inhibition was evaluated in an enzymatic system using human HNE, whereas antiradical activity was evaluated in a cell-based assay system using phorbol 12-myristate 13-acetate (PMA)-stimulated murine bone marrow leukocytes as the source of reactive oxygen species (ROS). HNE inhibition was due to the N-CO group targeting Ser195-OH at position 2 of the scaffold, while antiradical activity was due to the presence of the selenium atom. The most active compounds 4d, 4f, and 4j exhibited a good balance between anti-HNE (IC50 = 0.9-1.4 µM) and antiradical activity (IC50 = 0.05-0.7 µM). Additionally, the solid-state structure of 4d was determined and compared to that of the similar compound N-propionyl-1,2-benzisoselenazol-3(2H)-one.

Pyrene-Containing Polyamines as Fluorescent Receptors for Recognition of PFOA in Aqueous Media.

The globally widespread perfluorooctanoic acid (PFOA) is a concerning environmental contaminant, with a possible toxic long-term effects on the environment and human health The development of sensible, rapid, and low-cost detection systems is a current change in modern environmental chemistry. In this context, two triamine-based chemosensors, L1 and L2, containing a fluorescent pyrene unit, and their Zn(II) complexes are proposed as fluorescent probes for the detection of PFOA in aqueous media. Binding studies carried out by means of fluorescence and NMR titrations highlight that protonated forms of the receptors can interact with the carboxylate group of PFOA, thanks to salt bridge formation with the ammonium groups of the aliphatic chain. This interaction induces a decrease in the fluorescence emission of pyrene at neutral and slightly acidic pH values. Similarly, emission quenching has also been observed upon coordination of PFOA by the Zn(II) complexes of the receptors. These results evidence that simple polyamine-based molecular receptors can be employed for the optical recognition of harmful pollutant molecules, such as PFOA, in aqueous media.

Design, Synthesis and Pharmacological Evaluation of New Quinoline-Based Panx-1 Channel Blockers.

Pannexins are an interesting new target in medicinal chemistry, as they are involved in many pathologies such as epilepsy, ischemic stroke, cancer and Parkinson's disease, as well as in neuropathic pain. They are a family of membrane channel proteins consisting of three members, Panx-1, Panx-2 and Panx-3, and are expressed in vertebrates. In the present study, as a continuation of our research in this field, we report the design, synthesis and pharmacological evaluation of new quinoline-based Panx-1 blockers. The most relevant compounds 6f and 6g show an IC50 = 3 and 1.5 µM, respectively, and are selective Panx-1 blockers. Finally, chemical stability, molecular modelling and X-ray crystallography studies have been performed providing useful information for the realization of the project.

A Tetranuclear Copper(II)/Calcium(II) Complex as Dual Chemosensor for Colorimetric and Fluorescent Detection of Non-Steroidal Anti-Inflammatory Drugs.

The tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex based on Malten ligand has been investigated as a platform for anion binding. Simple organic carboxylates and non-steroidal anti-inflammatory drugs (NSAIDs) have been tested, revealing the ability of the platform to bind them. The receiving platform hosts at least two guests in solution although a third anion can be bound, as suggested by X-ray diffraction analysis. The addition of the anions is accompanied by a color change of the solution, making the system a colorimetric sensor for carboxylates (LOD values comprised between 3.6 and 20.7 ppm). A fluorescent system consisting of the 2-(3-oxido-6-oxoxanthen-9-yl)benzoate (fluorescein anion) linked to the tetranuclear platform has been also prepared and used in a chemosensing ensemble approach to signal the presence of the selected anions (Log K between 2.6 and 5.6 for the addition of two guests). The latter also works in a paper strip test, offering the chemosensor a possible practical application.

Sodium ß-Diketonate Glyme Adducts as Precursors for Fluoride Phases: Synthesis, Characterization and Functional Validation.

Very few sodium complexes are available as precursors for the syntheses of sodium-based nanostructured materials. Herein, the diglyme, triglyme, and tetraglyme (CH3O(CH2CH2O)nCH3, n = 2-4) adducts of sodium hexafluoroacetylacetonate were synthesized in a single-step reaction and characterized by IR spectroscopy, 1H, and 13C NMR. Single-crystal X-ray diffraction studies provide evidence of the formation of the ionic oligomeric structure [Na4(hfa)6]2-•2[Na(diglyme2]+ when the diglyme is coordinated, while a mononuclear seven-coordinated complex Na(hfa)•tetraglyme is formed with the tetraglyme. Reaction with the monoglyme (CH3OCH2CH2OCH3) does not occur, and the unadducted polymeric structure [Na(hfa)]n forms, while the triglyme gives rise to a liquid adduct, Na(hfa)•triglyme•H2O. Thermal analysis data reveal great potentialities for their applications as precursors in metalorganic chemical vapor deposition (MOCVD) and sol-gel processes. As a proof-of-concept, the Na(hfa)•tetraglyme adduct was successfully applied to both the low-pressure MOCVD and the sol-gel/spin-coating synthesis of NaF films.

Polyamine receptors containing anthracene as fluorescent probes for ketoprofen in H2O/EtOH solution.

Triamine receptors containing anthracene units are able to bind and sense ketoprofen via fluorescence enhancement in a H2O/EtOH 50 : 50 (Vol : Vol) mixture exploiting their protonation features, which are tuned by the interaction with the analyte.

Glyphosate sensing in aqueous solutions by fluorescent zinc(II) complexes of [9]aneN3-based receptors.

Herein we describe the binding abilities of Zn(II) complexes of [12]aneN4- (L1) and [9]aneN3-based receptors (L2, L3) towards the herbicides N-(phosphonomethyl)glycine (glyphosate, H3PMG) and 2-amino-4-[hydroxy(methyl)phosphoryl]butanoic acid (glufosinate, H2GLU), and also aminomethylphosphonic acid (H2AMPA), the main metabolite of H3PMG, and phosphate. All ligands form stable Zn(II) complexes, whose coordination geometries allow a possible interaction of the metal center with exogenous anionic substrates. Potentiometric studies evidenced the marked coordination ability of the L2/Zn(II) system for the analytes considered, with a preferential binding affinity for H3PMG over the other substrates, in a wide range of pH values. 1H and 31P NMR experiments supported the effective coordination of such substrates by the Zn(II) complex of L2, while fluorescence titrations and a test strip experiment were performed to evaluate whether the H3PMG recognition processes could be detected by fluorescence signaling.

Crystal Forms of the Antihypertensive Drug Irbesartan: A Crystallographic, Spectroscopic, and Hirshfeld Surface Analysis Investigation.

The design of new pharmaceutical solids with improved physical and chemical properties can be reached through in-detail knowledge of the noncovalent intermolecular interactions between the molecules in the context of crystal packing. Although crystallization from solutions is well-known for obtaining new solids, the effect of some variables on crystallization is not yet thoroughly understood. Among these variables, solvents are noteworthy. In this context, the present study aimed to investigate the effect of ethanol (EtOH), acetonitrile (MeCN), and acetone (ACTN) on obtaining irbesartan (IBS) crystal forms with 2,3-dibromosuccinic acid. Crystal structures were solved by single-crystal diffraction, and the intermolecular interactions were analyzed using the Hirshfeld surfaces analysis. The characterization of physicochemical properties was carried out by powder X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR), thermal analysis, and solution-state NMR techniques. Two different IBS salts were obtained, one from MeCN and ACTN (compound 1) and a different one from EtOH (compound 2). The experimental results were in agreement with the findings obtained through quantum mechanics continuum solvation models. Compound 1 crystallized as a monoclinic system P21/c, whereas compound 2 in a triclinic system P1̅. In both structures, a net of strong hydrogen bonds is present, and their existence was confirmed by the FT-IR results. In addition, the IBS cation acts as a H-bond donor through the N1 and N6 nitrogen atoms which interact with the bromide anion and the water molecule O1W in compound 1. Meanwhile, N1 and N6 nitrogen atoms interact with the oxygen atoms provided by two symmetry-related 2,3-dibromo succinate anions in compound 2. Solution-state NMR data agreed with the protonation of the imidazolone ring in the crystal structure of compound 1. Both salts presented a different thermal behavior not only in melting temperature but also in thermal stability.

Different Topologies of Hg(II)-Bispidine 1D Coordination Polymers: Dynamic Behavior in Solvent Adsorption and Exchange Processes.

One-dimensional (1D) coordination polymers (CPs) featuring three different topologies, comprising zig-zag, ribbon-like and poly-[n]-catenane structures, were obtained by reaction of Hg(II) ions with a novel bispidine ligand L3, and structurally characterized by SC- and P-XRD methods. The CPs obtained in the form of microcrystalline powders were tested for their ability to undergo solvent adsorption and exchange by P-XRD and 1 H NMR spectroscopy. The extent of their dynamic behavior was then correlated to their structural features, highlighting the role of interchain interactions established among their constituting linear arrays. Zig-zag CPs proved to be resilient to external chemical stimuli, while they differently respond to thermal treatments, depending on the solvent originally included within the CP. In the case of polycatenated structures, we observed transformations where the original topology was maintained upon guest exchange, but also cases where it changed to zig-zag, even under solid/vapor conditions (i. e., no complete dissolution of the CP). Given the presence of linear interconnected 1D channels, 3 ⋅ ClBz-polycatenanePwd is also able to trap volatile guests such as n-hexane when exposed to its vapors.

A selective fluorescent probe for gadoliniumIII in water based on a PdII-preorganized chromone-receptor.

The synthesis, solution studies, photochemical properties and the X-ray structure of a chromone based fluorescent PdII complex are reported. The ligand contains two chromone units linked as side arms to an ethylenediamine moiety; in the PdII complex the metal ion preorganizes the two hydroxychromone units forming a rigid structure with a negatively charged pocket formed by four oxygen atoms that is able to interact with hard metal cations, such as ions, giving rise to stable bimetallic complexes. Upon interaction with LaIII and GdIII, in particular, the emission intensity at 423 nm increases by a factor of 2 and 8, respectively, while the other rare earth ions quench the fluorescence. Spectrofluorimetric studies on real matrices showed the possibility to use this system as a selective fluorescence probe to detect and trace the presence of Gadolinium in environmental water acting as an OFF-ON chemosensor, with a LOD of 0.4 ppm and a LOQ of 1.2 ppm.

Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists.

N-formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.

Hetero-Tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ Architectures Based On Malten Ligand: Scaffold for Anion Binding.

The hetero-tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex obtained with the N,N'-bis((3-hydroxy-4-pyron-2-yl)methyl)-N,N'-dimethylethylendiamine (Malten) ligand has been studied in solid and solution states as scaffold to bind anions. Three crystal structures showing the same metal ions sequence have been examined; they display a tetracharged complex cation neutralized by four monocharged anions. The anions play two different roles: as coordinated (two ClO4- , Cl- or NO3- ) or ancillary (two ClO4- ) guests. The tetranuclear scaffold hosts two anions also in aqueous and ethanol solutions. Spectrophotometric studies in ethanol allowed to determine the addition constant values for Cl- and Br- (Log K1-2 =4.43(4), 4.39(3) for Cl- , 3.80(3), 3.54(2) for Br- ) while the others, although bound, showed lower affinity for the scaffold. Both the crystals and the solutions change their color depending on the added anion, namely pink, dark green or blue in the presence of ClO4- , Cl- or NO3- , respectively, thus the presence of the different anions is visible to the naked eye. The hetero-tetranuclear Cu2+ /Ca2+ /Ca2+ /Cu2+ complex is a versatile architecture to be used as scaffold for anion binding.

Zn(ii) detection and biological activity of a macrocycle containing a bis(oxadiazole)pyridine derivative as fluorophore.

The synthesis, photochemical properties, biological effects and the X-ray crystal structure of a fluorescent polyamine macrocycle L are reported. L is a polyamine cyclophane macrocycle in which 2,6-bis(5-(2-methylphenyl)-1,3,4-oxadiazol-2-yl)pyridine (POXAPy) acts as a fluorescent sensor and the polyamine as a metal ion binding unit. L performs as a PET-mediated chemosensor, with a maximum emission wavelength close to 360 nm. This gives rise to a signal that is visible to the naked eye in the blue visible range. L is able to detect the Zn(ii) and Cd(ii) metal ions in an aqueous solution at pH = 7, with the coordination of the ions switching the emission ON through a CHEF effect. In contrast, paramagnetic metal ions like Cu(ii) and Ni(ii) completely quench the already low emission of L at this pH value. L affects the cell survival of a leukemic cellular model (U937) at micromolar concentrations with cell death starting after only 24 h of exposure; starting from a final concentration of 5 µM, L almost completely abrogates the survival of the leukemic cells over 72 h, with a mechanism that is compatible with a genomic DNA interaction.

Switching on the Fluorescence Emission of Polypyridine Ligands by Simultaneous Zinc(II) Binding and Protonation.

The synthesis and characterization of the two new open-chain ligands 1,15-bis-[6-(2,2'-bipyridyl)]-2,5,8,11,14-pentaaza-octadecane (L1) and 1,15-bis-[2-(1,10-phenanthroline)-9-methyl]-2,5,8,11,14-pentaazaoctadecane (L2), both featuring a tetraethylenpentaamine chain linking via methylene bridges the 6 and 2 positions of two identical 2,2'-bipyridyl (bpy) and 9-methyl-1,10-phenanthroline (9-methyl-phen) moieties respectively, are reported. Their protonation and binding ability for Cu2+ , Zn2+ , Cd2+ and Pb2+ have been studied by coupling potentiometric titrations with UV-vis absorption and fluorescence emission measurements in water. L1 and L2 afford stable mono- and dinuclear complexes, in which the metal ion is bound by a single bpy or 9-methyl-phen unit and the amine groups on the aliphatic chain. However, L1 displays a greater binding ability for Cu2+ and Zn2+ with respect to L2, the stability constants of the [ML1]2+ complexes being 21.8 (Cu2+ ) and 19.4 (Zn2+ ) log units vs 20.34 and 16.8 log. units for the corresponding L2 species. Among all the metal ions tested, only the Zn2+ complex with L2 features an enhanced fluorescence emission at neutral pH, thanks to the simultaneous binding of one Zn2+ ion and H+ ion(s), that inhibits any possible photoinduced electron transfer (PET) process from the amine donors to the excited phen moiety. Binding of a second metal switches off the emission again.

Zn2+ and Cu2+ complexes of a fluorescent scorpiand-type oxadiazole azamacrocyclic ligand: crystal structures, solution studies and optical properties.

A ligand comprised of a macrocyclic pyridinophane core having a pendant arm containing a secondary amine group linked through a methylene spacer to a pyridyl-oxadiazole-phenyl (PyPD) fluorescent system has been prepared (L). The crystal structures of [ZnL](ClO4)2 and [CuL](ClO4)2 show that M2+ is coordinated to all the nitrogen atoms of the macrocyclic core, the secondary amine of the pendant arm and the nitrogen atom of the pyridine group of the fluorescent moiety, the latter bond being clearly weaker than the one with the pyridine of the macrocycle. Solution studies showed the formation of a highly stable Cu2+ complex with 1 : 1 stoichiometry, whereas with Zn2+ least stable complexes were formed and, given the right conditions, a [Zn3L2]6+ species was also detected, but it was not possible to isolate this species in the solid state. Following Zn2+ coordination, a strong chelation-induced enhancement of fluorescence was observed, a behaviour that was not observed with any of the other metal cations tested.

Facile synthesis of novel lithium ß-diketonate glyme adducts: the effect of molecular engineering on the thermal properties.

Novel adducts of lithium hexafluoroacetylacetonato {Li(hfa)} with polyethers (monoglyme = {CH3OCH2CH2OCH3}, diglyme = {CH3O(CH2CH2O)2CH3}, triglyme = {CH3O(CH2CH2O)3CH3} and tetraglyme {CH3O(CH2CH2O)4CH3} have been synthesized through a single step reaction and characterized by FT-IR spectroscopy, 1H, and 13C NMR, single crystal X-ray diffraction studies along with thermal analysis.

New 3-unsubstituted isoxazolones as potent human neutrophil elastase inhibitors: Synthesis and molecular dynamic simulation.

Human neutrophil elastase (HNE) is a proteolytic enzyme belonging to the serine protease family and is involved in a variety of pathologies. Thus, compounds able to inhibit HNE represent promising therapeutics for the treatment of inflammatory diseases. Here, we report the further elaboration of our previously reported 3-methylisoxazolone derivatives, synthesizing a new series of 3-nor-derivatives bearing different substituents at the 4-phenyl ring. The most potent compounds 3a, 3g, and 3h, had IC50 values of 16, 11, and 18 nM, respectively. Molecular modeling studies and molecular dynamic (MD) simulations demonstrated no substantial differences between the 3-methylisoxazole derivatives previously tested and the corresponding 3-unsubstituted derivatives in the snapshot conformations sampled during the MD simulations, which is consistent with their similar levels of HNE inhibitory activity. Thus, we conclude that the isoxazolone scaffold is a good scaffold for developing HNE inhibitors, as it tolerates several modifications when adhering to basic scaffold requirements, and the resulting derivatives are quite potent HNE inhibitors.

The role of solid state properties on the dissolution performance of flufenamic acid.

Flufenamic acid is a nonsteroidal anti-inflammatory drug characterized by a low solubility and a variable oral bioavailability. Flufenamic acid is present in the commercial products in two polymorphic enantiotropic forms (Form I and III). Bioinequivalence was observed for commercial solid dosage forms due to the different dissolution rate of batches. Aim of this work is the full characterization of the solid state properties of flufenamic acid in order to evidence reasons of its variable dissolution properties. Two different batches of pure drug obtained by different suppliers were fully characterized. In order to evaluate the effect of the technological processes used for tablet production, the powders were submitted to grinding, kneading, and compression. Thermal analysis and X-ray diffraction studies proved that the drug was provided by both suppliers as Form I, Form III is obtained by recrystallization from ethanol or ethanol/water of both batches and no changes were observed after the different mechanical treatments. No difference was observed between the two forms in terms of equilibrium solubility values. Dissolution rate studies evidenced a difference between the two batches due to their different particle size, which disappeared after sieving. Interestingly, a significant difference in terms of intrinsic dissolution rate and surface wettability of the two compacted powders was observed, even after sieving, probably related to a different behavior of the two powder samples under compaction. These results should be taken into account, during a tablet formulation, in order to obtain a reproducible dissolution performance of the drug, regardless of its original supplier.

A new crystal form of the NSAID dexketoprofen.

Dexketoprofen [(2S)-2-(3-benzoylphenyl)propanoic acid], C16H14O3, is the S-enantiomer of ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, antipyretic and anti-inflammatory properties, and finds applications for the short-term treatment of mild to moderate pain. A new crystalline phase of dexketoprofen is reported. Its solid-state structure was determined by single-crystal X-ray diffraction (SCXRD). The molecular structure of the two independent molecules found in the asymmetric unit of this new phase (DXKP-ß) were compared to those of the already known crystal form of dexketoprofen (DXKP-α) and with the S-enantiomer of the racemic compound. The three different conformers of dexketoprofen found in DXKP-α and DXKP-ß were then investigated by computational methods. The optimized structures are very close to the corresponding starting geometries and do not differ significantly in energy. The crystal packing of DXKP-ß was studied by means of Hirshfeld surface (HS) analysis; interaction energies were also calculated. A comparison with DXKP-α shows close similarities between the two crystal forms, i.e. in both cases, molecules assemble through the catemer O-H...O synthon of the carboxylic acid stabilized by additional C-H...O contacts and, accordingly, the interaction energies, as well as the contributions to the HS area, are very similar. Finally, the thermal behaviour of the two polymorphs of dexketoprofen was assessed by means of XRD (both from single crystal and microcrystalline powder) and differential scanning calorimetry (DSC); both crystal forms are stable under the experimental conditions adopted (air, 300-350 K for DXKP-α and 300-340 K DXKP-ß) and no solid-solid phase transition occurs between the two crystal forms in the investigated temperature range (from 100 K up to ca 350 K).