C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies.

Protein phosphatase 2A (PP2A) is an important Ser/Thr phosphatase that participates in the regulation of multiple cellular processes. This implies that any deficient activity of PP2A is the responsible of severe pathologies. For instance, one of the main histopathological features of Alzheimer's disease is neurofibrillary tangles, which are mainly comprised by hyperphosphorylated forms of tau protein. This altered rate of tau phosphorylation has been correlated with PP2A depression AD patients. With the goal of preventing PP2A inactivation in neurodegeneration scenarios, we have aimed to design, synthesize and evaluate new ligands of PP2A capable of preventing its inhibition. To achieve this goal, the new PP2A ligands present structural similarities with the central fragment C19-C27 of the well-established PP2A inhibitor okadaic acid (OA). Indeed, this central moiety of OA does not exert inhibitory actions. Hence, these compounds lack PP2A-inhibiting structural motifs but, in contrast, compete with PP2A inhibitors, thus recovering phosphatase activity. Proving this hypothesis, most compounds showed a good neuroprotective profile in neurodegeneration models related to PP2A impairment, highlighting derivative 10, named ITH12711, as the most promising one. This compound (1) restored in vitro and cellular PP2A catalytic activity, measured on a phospho-peptide substrate and by western-blot analyses, (2) proved good brain penetration measured by PAMPA, and (3) prevented LPS-induced memory impairment of mice in the object recognition test. Thus, the promising outcomes of the compound 10 validate our rational approach to design new PP2A-activating drugs based on OA central fragment.

Cellulose/pectin-based materials incorporating Laponite-indole derivative hybrid for oral administration and controlled delivery of the neuroprotective drug.

Bionanocomposite materials based on clays have been designed for oral administration and controlled release of a neuroprotective drug derivative of 5-methylindole, which had featured an innovative pharmacological mechanism for the treatment of neurodegenerative diseases such as Alzheimer's. This drug was adsorbed in the commercially available Laponite® XLG (Lap). X-ray diffractograms confirmed its intercalation in the interlayer region of the clay. The loaded drug was 62.3 meq/100 g Lap, close to the cation exchange capacity of Lap. Per se toxicity studies and neuroprotective experiments versus the neurotoxin okadaic acid, a potent and selective inhibitor of protein phosphatase 2A (PP2A), confirmed that the clay-intercalated drug did not exert toxicity in cell cultures and provided neuroprotection. Release tests of the hybrid material performed in media mimicking the gastrointestinal tract indicated a drug release in acid medium close to 25 %. The hybrid was encapsulated in a micro/nanocellulose matrix and processed as microbeads, with pectin coating for additional protection, to minimize release under acidic conditions. Alternatively, low density materials based on a microcellulose/pectin matrix were evaluated as orodispersible foams showing fast disintegration times, sufficient mechanical resistance for handling, and release profiles in simulated media that confirmed a controlled release of the encapsulated neuroprotective drug.

Azaindole grafted titanium dioxide for the photodegradation of pharmaceuticals under solar irradiation.

The application of metal-free organic molecules grafted titanium dioxide (TiO2) as photocatalysts for the degradation of pharmaceuticals under solar light has been scarcely studied. Herein, a novel photocatalyst was synthesized anchoring a bipolar electron-donor and -acceptor molecule based on azaindole derivative (AZA4) onto TiO2 aiming to improve the photoactivity under simulated solar irradiation. The TiO2-azaindole (TiO2-AZA4) was fully characterized, confirming that AZA4 was successfully grafted onto TiO2 and improving the light absorption. The grafted TiO2 was applied in the photodegradation of acetaminophen in water, showing a significantly better photocatalytic performance compared to that of pure TiO2 under both solar and visible irradiations. AZA4 grafting leads to the TiO2 band gap narrowing and favors the charge separation, thus improving the TiO2 photoactivity. The photocatalytic performance of TiO2-AZA4 was evaluated using different conditions such as photocatalyst dose or initial pH of the solution, and the radical species involved in the process were investigated. The high activity of TiO2-AZA4 was confirmed in the photodegradation of a mixture of pharmaceuticals, namely acetaminophen, ibuprofen, and antipyrine, further demonstrating its stability and catalytic performance in a novel continuous flow test under simulated solar irradiation, thus finding a new strategy to design solar-light driven photocatalysts for the degradation of pollutants in water.

(±)-BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3ß Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.

Organic Semiconductor Micro/Nanocrystals for Laser Applications.

Organic semiconductor micro/nanocrystals (OSMCs) have attracted great attention due to their numerous advantages such us free grain boundaries, minimal defects and traps, molecular diversity, low cost, flexibility and solution processability. Due to all these characteristics, they are strong candidates for the next generation of electronic and optoelectronic devices. In this review, we present a comprehensive overview of these OSMCs, discussing molecular packing, the methods to control crystallization and their applications to the area of organic solid-state lasers. Special emphasis is given to OSMC lasers which self-assemble into geometrically defined optical resonators owing to their attractive prospects for tuning/control of light emission properties through geometrical resonator design. The most recent developments together with novel strategies for light emission tuning and effective light extraction are presented.

In Silico Prediction of the Toxic Potential of Neuroprotective Bifunctional Molecules Based on Chiral N-Propargyl-1,2-amino Alcohol Derivatives.

N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities. We obtained several neuroprotective molecules, chiral 1,2-amino alcohols and 1,2-diamines, able to reduce by almost 70% the rotenone and oligomycin A-induced damage in SH-SY5Y cells. Furthermore, some molecules assessed also counteracted the toxicity evoked by the Ser/Thr phosphatase inhibitor okadaic acid. Before extrapolating these data to preclinical studies, we analyze the molecules through an in silico prediction system to detect carcinogenicity risk or other toxic effects. In light of these promising results, these molecules may be considered as a lead family of neuroprotective and relatively safe compounds.

Synthesis and photophysical studies of an indigo derivative: N-octyl-7,7'-diazaindigo.

In this paper, we explore the synthesis, characterization, and photophysical properties of a novel indigo derivative, N-octyl-7,7'-diazaindigo, being the first time that diazaindigos have been studied as photophysically-active chemical entities. Reduction of the neutral "keto-form" to the so-called "leuco-form" changes the global spectroscopic and photophysical behaviors. Both species have been investigated by different photophysical studies, such as analysis of absorption and emission spectra, fluorescence quantum yields (Φ F) and lifetimes. Finally, to appraise in depth the deactivation of the excited state of the keto form, femtosecond transient absorption (TA) experiments and Density Functional Theory (DFT) and Time Dependent (TD)-DFT calculations were performed. In an organic aprotic solvent (N,N-dimethylformamide), TA experiments showed a fast deactivation channel (τ 1 = 2.9 ps), which was ascribed to solvent reorganization, and a longer decay component (τ 2 = 86 ps) associated with an internal conversion (IC) process to the ground-state, in opposition to the excited state proton transfer (ESPT) mechanism that takes place in the indigo molecules but in protic solvents. A comparative study was also carried out on the parent molecule, 7,7'-diazaindigo, corroborating the previous conclusions obtained for the alkyl derivative. In agreement with experimental observations, DFT and TD-DFT calculations revealed that the deactivation of the S1 state of the keto form takes place through an internal conversion process.

Design and synthesis of multipotent 3-aminomethylindoles and 7-azaindoles with enhanced protein phosphatase 2A-activating profile and neuroprotection.

We report the synthesis and pharmacological evaluation of new 3-aminomethylindoles derivatives with neuroprotective properties designed to present multi-target activity centered on reducing the neuronal Ca2+ overload and preventing phosphatase 2A (PP2A) inhibition, which are two important early physiophathological events observed in neurodegenerative scenarios. Chemical syntheses of proposed compounds were achieved in two straightforward reaction steps with high yields. Most of the compounds mitigated the okadaic acid-provoked inhibition of PP2A and protected SH-SY5Y cells against toxic stimuli related to Tau-hyperphosphorylation and oxidative stress, similarly to the observed in Alzheimer's disease (AD). In addition, some of them mitigated the Ca2+ overload induced by depolarization. The derivative 1-(1-benzyl-5-chloro-1H-indol-3-yl)-N,N-dimethylmethanamine (19) outstood by its high recovery of the PP2A activity and blockade of voltage-gated Ca2+ channels, accompanied by good neuroprotective profile. These findings make this compound eligible for further preclinical assays with the goal of positioning new innovative drugs for the treatment of AD.

Mobility versus Alignment of a Semiconducting π-Extended Discotic Liquid-Crystalline Triindole.

The p-type semiconducting properties of a triphenylene-fused triindole mesogen, have been studied by applying two complementary methods which have different alignment requirements. The attachment of only three flexible alkyl chains to the nitrogen atoms of this π-extended core is sufficient to induce columnar mesomorphism. High hole mobility values (0.65 cm2 V-1 s-1) have been estimated by space-charge limited current (SCLC) measurements in a diode-like structure which are easily prepared from the melt, rendering this material a good candidate for OPVs and OLEDs devices. The mobility predicted theoretically via a hole-hopping mechanism is in very good agreement with the experimental values determined at the SCLC regime. On the other hand the hole mobility determined on solution processed thin film transistors (OFETs) is significantly lower, which can be rationalized by the high tendency of these large molecules to align on surfaces with their extended π-conjugated core parallel to the substrate as demonstrated by SERS. Despite the differences obtained with the two methods, the acceptable performance found on OFETs fabricated by simple drop-casting processing of such an enlarged aromatic core is remarkable and suggests facile hopping between neighboring molecular columns owing to the large conducting/isolating ratio found in this discotic compound.

Aggregation-Induced Emission of Organogels Based on Self-Assembled 5-(4-Nonylphenyl)-7-azaindoles.

A new self-assembled organogel based on 5-(4-nonylphenyl)-7-azaindole (1), possessing an aggregation-induced emission phenomenon (AIE), is described. The incorporation of phenyl alkyl chains improves processability of the platform to form a new class of gelator. The fluorescence spectrum of 1 suffers changes in the gelation process, and an AIE phenomenon is observed during the phase transition from sol to gel state. The fluorescence is decreased slowly by heating the gel, and no emission is detected in concentrated solutions of 1. The AIE effect is due to the formation of the supramolecular organogel, where a self-association of the 7-azaindole moieties by dual hydrogen-bonded dimers is present. Regarding the solid-state emission properties, the xerogel 1 exhibits blue emission as well as in its organogel form. Therefore, it could be considered as a promising blue emitter in the solid state.

Nonlinear optical thin film device from a chiral octopolar phenylacetylene liquid crystal.

A set of chiral discotic phenylacetylenes have been synthesized by 3-fold Sonogashira coupling between different ethynylbenzenes and triiodobenzenes. The resultant bulk materials are fully characterized by polarized optical microscopy (POM), differential scanning calorimetry (DSC), and X-ray diffraction. The octopolar nature of the target compounds is studied by UV-vis absorption spectroscopy and hyper-Raleigh scattering in solution. Optimization of the donor-acceptor substitution yields both high hyperpolarizability values and appreciable mesomorphic properties. A simple thin film device for second harmonic generation has been prepared from the nitro-substituted liquid crystalline derivative.

Organic Semiconductors toward Electronic Devices: High Mobility and Easy Processability.

Chemists worldwide are making strong efforts toward finding an organic semiconductor with optimum charge-transport stability and processability properties, approaching the problem from several angles. The number and variety of organic semiconductors have expanded exponentially during the past few years, allowing their classification and identification of the advantages and drawbacks of the different candidates, and leading to an increasingly better understanding of factors affecting charge carrier mobility. In this Perspective, we present different types of materials available, classified according to their supramolecular order. As it will be shown, high intermolecular order, although beneficial for charge transport, may compromise processability. The required balance between processing and high mobility can be achieved only through an adequate design at both the molecular and supramolecular levels.

Self-assembly of C3-symmetrical hexaaryltriindoles driven by solvophobic and CH-pi interactions.

The synthesis and aggregation properties of a series of differently substituted star-shaped hexaaryltriindoles both in solution and in the solid state are being reported. While these molecules do not show any significant intermolecular aggregation in CDCl(3), it has been possible to induce aggregation by increasing the polarity of the solvent and therefore facilitating the occurrence of solvophobic forces. A study of the influence of the electronic character of peripheral substituents on the self-association behavior in solution has shown that increasing the electron-donor character of the substituents facilitates self-association while derivatives substituted with electron-acceptor substituents do not self-assemble. The electronic nature of the substituents also has an influence in the geometry of the stacking of these derivatives observed in the solid state. While unsubstituted hexaphenyl triindole self-assemble in a staggered face-to-face arrangement, attaching six cyano functional groups results in an offset stacking. The influence of the substituents in the strength and geometry of the stacking tendency contrasts with the trend expected for an aggregation induced solely by pi-pi interactions, but can be explained considering an important contribution of multiple cooperative CH-pi interactions.

Synthesis and preferred all-syn conformation of C3-symmetrical N-(hetero)arylmethyl triindoles.

A new series of C(3)-symmetrical N-(hetero)arylmethyl triindoles has been synthesized in a straightforward procedure. The structure and conformation in the solid state have been determined for three derivatives (3, 4, and 6) by X-ray crystallographic analysis. In all three cases, the molecules adopt a tripodal conformation with all of the flexible arms directed towards the same side, thereby delimiting an inner cavity. Compound 6 crystallizes and forms C(3)-symmetric dimeric cagelike complexes. Guest molecules of chloroform and water are confined within the resulting cavities with stabilization by different intermolecular interactions; this highlights the potential of these compounds in the construction of supramolecular systems. A computational analysis has been performed to predict the most stable conformers. As a general trend, a preference for a conformation with all branches directed to the same side has been predicted. Comparison between theoretical and experimental results indicates that the computational level selected for the present study, B3LYP/6-31G*, is able to reproduce both the minimum energy conformations and the rotation barriers about the N--CH(2) bond.

Synthesis and self-association properties of functionalized C3-symmetric hexakis(p-substituted-phenylethynyl)triindoles.

A number of differently substituted phenylethynyl triindoles has been synthesized by 6-fold Sonogashira coupling in a key step. This new series of hexaalkynyl triindoles self-associate through arene-arene interactions in solution. The electronic communication of the external substituents with the central electron-rich triindole core has been demonstrated by means of cyclic voltammetry and optical absorption. A study of the effect of the electronic character of peripheral substituents on their self-association behavior is presented in an effort to shed light on the nature of the pi-stacking interactions.

Synthesis of diiodo butadiynyl-bridged bisphthalocyaninatozinc(II) complexes.

Two functionalized phthalocyanine-based chromophore systems having two iodophthalocyaninatozinc(II) rings bound together through a butadiynyl linkage 1a,b have been synthesized by oxidative Eglinton coupling of the corresponding monomer, and fully characterized. The electronic characteristics of these extensively linearly pi-conjugated compounds were modulated by the introduction of different peripheral substituents into the phthalocyanine moieties and investigated by UV-visible spectroscopy. The reactivity of the two iodo substituents was explored to prepare a novel bisphthalocyanine containing two ethynylphenyl moieties, thus pointing out the possibility of incorporating other electro and/or photoactive moieties in the BisPc system, taking advantage of the iodo-functionalization.

Unusual mesomorphic behaviour of an ethynyl-substituted phthalocyanine.

An ethynyl-substituted nickel(II) phthalocyanine has been synthesised and its thermotropic properties studied; optical microscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques revealed an unusual mesomorphic behaviour observed for the first time in phthalocyanine systems where each disk of the hexagonal columnar mesophase is formed by two ethynyl-substituted phthalocyanine units.

Synthesis and properties of cobalt(III) complexes of 4-substituted pyridine-capped dioxocyclams.

Cobalt(III) acetate and cyanide complexes of a series of 5,12-dioxocyclams capped across the 1,8-position by 4-substituted pyridines or pyrazine were synthesized and fully characterized. Both the spectroscopic and structural parameters for these complexes were remarkably insensitive to the electronic nature of the capping group, which ranged from the pi-accepting pyrazine group to the sigma-donating 4-[(dimethylamino)phenyl]pyridyl group. All of the complexes underwent an irreversible, one-electron reduction [Co(III)-->Co(II)] at potentials ranging from -0.95 V vs saturated calomel electrode (SCE) for the pyrazine-capped cobalt acetate complex to -1.36 V vs SCE for the pyridine-capped cobalt cyanide complexes. Pyridine-capped cobalt(III) cyanide complex underwent reaction with Rh2(OAc)4 and ruthenium(II) phthalocyanine[bis(benzonitrile)] to form tetrametallic and trimetallic complexes through coordination bridging by the cyanide nitrogen lone pair. These complexes represent two quite different structural types for cyanide-bridged polymetallics. Complex has a relatively long (2.192 A) cyanide N-to-Rh bond, and the CN-Rh bond angle (157.6 degrees) is strongly distorted from linear. In contrast, complex has a substantially shortened cyanide N-to-Ru bond (2.017 A) and an almost linear arrangement along the entire bridging axis of the molecule.