Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.

New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)-5a-v, (±)-6a-j, and (±)-7a-d) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-5d, (±)-5l, and (±)-5r. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. 5v was identified as selective for MAGL when compared with other serine hydrolases. Solubility, in vitro metabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((±)-5c, (±)-5d, and (±)-5v) were used for in vivo studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl-sn-glycerol levels in forebrain tissue. In particular, 5v is characterized by a high eudysmic ratio and (3R,4S)-5v is one of the most potent irreversible inhibitors of h/mMAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

Fully printed memristors made with MoS2 and graphene water-based inks.

2-Dimensional materials (2DMs) offer an attractive solution for the realization of high density and reliable memristors, compatible with printed and flexible electronics. In this work we fabricate a fully inkjet printed MoS2-based resistive switching memory, where graphene is used as top electrode and silver is used as bottom electrode. Memristic effects are observed only after annealing of each printed component. The printed memory on silicon shows low SET/RESET voltage, short switching times (less than 0.1 s) and resistance switching ratios of 103-105, comparable or superior to the performance obtained in devices with both printed silver electrodes on rigid substrates. The same device on Kapton shows resistance switching ratios of 102-103 and remains stable at least up to 2% of strain. The memristor resistance switching is attributed to the formation of Ag conductive filaments, which can be suppressed by integrating graphene grown by chemical vapour deposition (CVD) onto the silver electrode. Temperature-dependent electrical measurements starting from 200 K show that memristic behavior appears at a temperature of ∼300 K, confirming that an energy threshold is needed to form the conductive filament. This work shows that inkjet printing is a very powerful technique for the fabrication of 2DMs-based resistive switches onto rigid and flexible substrates.

Electronics and Detectors for the Stellar Intensity Interferometer of the ASTRI Mini-Array Telescopes.

The ASTRI Mini-Array is an international collaboration led by the Italian National Institute for Astrophysics (INAF) that will operate nine telescopes to perform Cherenkov and optical stellar intensity interferometry (SII) observations. At the focal plane of these telescopes, we are planning to install a stellar intensity interferometry instrument. Here we present the selected design, based on Silicon Photomultiplier (SiPM) detectors matching the telescope point spread function together with dedicated front-end electronics.

Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors.

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

Etch and Print: Graphene-Based Diodes for Silicon Technology.

The graphene-silicon junction is one of the simplest conceivable interfaces in graphene-integrated semiconductor technology that can lead to the development of future generation of electronic and optoelectronic devices. However, graphene's integration is currently expensive and time-consuming and shows several challenges in terms of large-scale device fabrication, effectively preventing the possibility of implementing this technology into industrial processes. Here, we show a simple and cost-effective fabrication technique, based on inkjet printing, for the realization of printed graphene-silicon rectifying devices. The printed graphene-silicon diodes show an ON/OFF ratio higher than 3 orders of magnitude and a significant photovoltaic effect, resulting in a fill factor of ∼40% and a photocurrent efficiency of ∼2%, making the devices suitable for both electronic and optoelectronic applications. Finally, we demonstrate large-area pixeled photodetectors and compatibility with back-end-of-line fabrication processes.

Graphene-Silicon Device for Visible and Infrared Photodetection.

The fabrication of a graphene-silicon (Gr-Si) junction involves the formation of a parallel metal-insulator-semiconductor (MIS) structure, which is often disregarded but plays an important role in the optoelectronic properties of the device. In this work, the transfer of graphene onto a patterned n-type Si substrate, covered by Si3N4, produces a Gr-Si device, in which the parallel MIS consists of a Gr-Si3N4-Si structure surrounding the Gr-Si junction. The Gr-Si device exhibits rectifying behavior with a rectification ratio up to 104. The investigation of its temperature behavior is necessary to accurately estimate the Schottky barrier height (SBH) at zero bias, φb0 = 0.24 eV, the effective Richardson's constant, A* = 7 × 10-10 AK-2 cm-2, and the diode ideality factor n = 2.66 of the Gr-Si junction. The device is operated as a photodetector in both photocurrent and photovoltage mode in the visible and infrared (IR) spectral regions. A responsivity of up to 350 mA/W and an external quantum efficiency (EQE) of up to 75% are achieved in the 500-1200 nm wavelength range. Decreases in responsivity to 0.4 mA/W and EQE to 0.03% are observed above 1200 nm, which is in the IR region beyond the silicon optical band gap, in which photoexcitation is driven by graphene. Finally, a model based on two parallel and opposite diodes, one for the Gr-Si junction and the other for the Gr-Si3N4-Si MIS structure, is proposed to explain the electrical behavior of the Gr-Si device.

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents.

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor 2a. When tested in two rodent models of epilepsy, 2a reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, 2a did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (3a-m). Biological studies highlighted 3h and 3m as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, 3h and 3m could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for 3h (Langendorff perfused rat heart). Finally, the new analogue 3h reduced the severity of the pilocarpine-induced status epilepticus as observed for 2a.

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation.

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit 6a. We identified compound 6j as the most potent and selective hHDAC6 inhibitor of the series. Biological investigation of compounds 6b, 6h, and 6j demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. 6j induced HDAC6-dependent pSTAT3 inhibition.

Design, Synthesis, and X-ray Studies of Potent HIV-1 Protease Inhibitors with P2-Carboxamide Functionalities.

The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-state isosteres. A number of inhibitors showed excellent HIV-1 protease inhibitory and antiviral activity; however, ligand combination is critical for potency. Inhibitor 4h with a difluorophenylmethyl as the P1 ligand, crown-THF-derived acetamide as the P2 ligand, and a cyclopropylaminobenzothiazole P2'-ligand displayed very potent antiviral activity and maintained excellent antiviral activity against selected multidrug-resistant HIV-1 variants. A high resolution X-ray structure of inhibitor 4h-bound HIV-1 protease provided molecular insight into the binding properties of the new inhibitor.

Electron Irradiation of Metal Contacts in Monolayer MoS2 Field-Effect Transistors.

Metal contacts play a fundamental role in nanoscale devices. In this work, Schottky metal contacts in monolayer molybdenum disulfide (MoS2) field-effect transistors are investigated under electron beam irradiation. It is shown that the exposure of Ti/Au source/drain electrodes to an electron beam reduces the contact resistance and improves the transistor performance. The electron beam conditioning of contacts is permanent, while the irradiation of the channel can produce transient effects. It is demonstrated that irradiation lowers the Schottky barrier at the contacts because of thermally induced atom diffusion and interfacial reactions. The simulation of electron paths in the device reveals that most of the beam energy is absorbed in the metal contacts. The study demonstrates that electron beam irradiation can be effectively used for contact improvement through local annealing.

WS2 Nanotubes: Electrical Conduction and Field Emission Under Electron Irradiation and Mechanical Stress.

This study reports the electrical transport and the field emission properties of individual multi-walled tungsten disulphide (WS2 ) nanotubes (NTs) under electron beam irradiation and mechanical stress. Electron beam irradiation is used to reduce the nanotube-electrode contact resistance by one-order of magnitude. The field emission capability of single WS2 NTs is investigated, and a field emission current density as high as 600 kA cm-2 is attained with a turn-on field of ≈100 V µm-1 and field-enhancement factor ≈50. Moreover, the electrical behavior of individual WS2 NTs is studied under the application of longitudinal tensile stress. An exponential increase of the nanotube resistivity with tensile strain is demonstrated up to a recorded elongation of 12%, thereby making WS2 NTs suitable for piezoresistive strain sensor applications.

Observation of 2D Conduction in Ultrathin Germanium Arsenide Field-Effect Transistors.

We report the fabrication and electrical characterization of germanium arsenide (GeAs) field-effect transistors with ultrathin channels. The electrical transport is investigated in the 20-280 K temperature range, revealing that the p-type electrical conductivity and the field-effect mobility are growing functions of temperature. An unexpected peak is observed in the temperature dependence of the carrier density per area at ∼75 K. Such a feature is explained considering that the increased carrier concentration at higher temperatures and the vertical band bending combined with the gate field lead to the formation of a two-dimensional (2D) conducting channel, limited to few interfacial GeAs layers, which dominates the channel conductance. The conductivity follows the variable-range hopping model at low temperatures and becomes the band-type at higher temperatures when the 2D channel is formed. The formation of the 2D channel is validated through a numerical simulation that shows excellent agreement with the experimental data.

Bias Tunable Photocurrent in Metal-Insulator-Semiconductor Heterostructures with Photoresponse Enhanced by Carbon Nanotubes.

Metal-insulator-semiconductor-insulator-metal (MISIM) heterostructures, with rectifying current-voltage characteristics and photosensitivity in the visible and near-infrared spectra, are fabricated and studied. It is shown that the photocurrent can be enhanced by adding a multi-walled carbon nanotube film in the contact region to achieve a responsivity higher than 100   mA   W - 1 under incandescent light of 0.1   mW   cm - 2 . The optoelectrical characteristics of the MISIM heterostructures are investigated at lower and higher biases and are explained by a band model based on two asymmetric back-to-back Schottky barriers. The forward current of the heterojunctions is due to majority-carrier injection over the lower barrier, while the reverse current exhibits two different conduction regimes corresponding to the diffusion of thermal/photo generated carriers and majority-carrier tunneling through the higher Schottky barrier. The two conduction regimes in reverse bias generate two plateaus, over which the photocurrent increases linearly with the light intensity that endows the detector with bias-controlled photocurrent.

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D2 or D3 receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.

Synthesis, biological evaluation and molecular modeling of novel selective COX-2 inhibitors: sulfide, sulfoxide, and sulfone derivatives of 1,5-diarylpyrrol-3-substituted scaffold.

A novel series of 1,5-diarylpyrrol-3-sulfur derivatives (10-12) was synthesized and characterized by NMR and mass spectroscopy and x-ray diffraction. The biological activity of these compounds was evaluated in in vitro and in vivo tests to assess their COX-2 inhibitory activity along with anti-inflammatory and antinociceptive effect. Results showed that the bioisosteric transformation of previously reported alkoxyethyl ethers (9a-c) into the corresponding alkyl thioethers (10a-c) still leads to selective and active compounds being the COX-2 inhibitory activity for most of them in the low nanomolar range. The oxidation products of 10a,b were also investigated and both couple of sulfoxides (11a,b) and sulfones (12a,b) showed an appreciable COX-2 inhibitory activity. Molecular modeling studies were performed to investigate the binding mode of the representative compounds 10b, 11b, and 12b into COX-2 enzyme and to explore the potential site of metabolism of 10a and 10b due to the different in vivo efficacy. Among the developed compounds, compound 10b showed a significant in vivo anti-inflammatory and antinociceptive activity paving the way to develop novel anti-inflammatory drugs.

Field Emission Characterization of MoS2 Nanoflowers.

Nanostructured materials have wide potential applicability as field emitters due to their high aspect ratio. We hydrothermally synthesized MoS2 nanoflowers on copper foil and characterized their field emission properties, by applying a tip-anode configuration in which a tungsten tip with curvature radius down to 30-100 nm has been used as the anode to measure local properties from small areas down to 1-100 µm2. We demonstrate that MoS2 nanoflowers can be competitive with other well-established field emitters. Indeed, we show that a stable field emission current can be measured with a turn-on field as low as 12 V/µm and a field enhancement factor up to 880 at 0.6 µm cathode-anode separation distance.

Graphene Schottky Junction on Pillar Patterned Silicon Substrate.

A graphene/silicon junction with rectifying behaviour and remarkable photo-response was fabricated by transferring a graphene monolayer on a pillar-patterned Si substrate. The device forms a 0.11 eV Schottky barrier with 2.6 ideality factor at room temperature and exhibits strongly bias- and temperature-dependent reverse current. Below room temperature, the reverse current grows exponentially with the applied voltage because the pillar-enhanced electric field lowers the Schottky barrier. Conversely, at higher temperatures, the charge carrier thermal generation is dominant and the reverse current becomes weakly bias-dependent. A quasi-saturated reverse current is similarly observed at room temperature when the charge carriers are photogenerated under light exposure. The device shows photovoltaic effect with 0.7% power conversion efficiency and achieves 88 A/W photoresponsivity when used as photodetector.

Asymmetric Diels-Alder reaction of 3-(acyloxy) acryloyl oxazolidinones: optically active synthesis of a high-affinity ligand for potent HIV-1 protease inhibitors.

We describe here our investigation of the asymmetric Diels-Alder reaction of chiral 3-(acyloxy)acryloyl oxazolidinones as dienophiles in various Lewis-acid promoted reactions with cyclopentadiene. The resulting highly functionalized cycloadducts are useful intermediates for the synthesis, particularly for the optically active synthesis of 6-5-5 tricyclic hexahydro-4H-3,5-methanofuro[2,3-b]pyranol (3) with five contiguous chiral centers. This stereochemically defined crown-like heterocyclic derivative is an important high affinity ligand for a variety of highly potent HIV-1 protease inhibitors. Among the various dienophiles and Lewis acid-mediated reactions surveyed, 3-(4-methoxybenzoyl)acryloyl oxazolidinone as the dienophile and diethylaluminum chloride as the Lewis-acid provided the desired endo product with excellent diastereoselectivity. The cycloaddition was carried out in multi-gram scale and the cycloadduct was efficiently converted to alcohol 3 with high enantiomeric purity. The optically active ligand was then transformed into potent HIV-1 protease inhibitor 2.

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents.

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.

Cinnamic acids derived compounds with antileishmanial activity target Leishmania amazonensis arginase.

This study describes the activity of five natural hydroxycinnamic acids and derived compound: caffeic (1), rosmarinic (2), chlorogenic (3), and cryptochlorogenic (4), acids and isoverbascoside (5). All compounds inhibited Leishmania amazonensis arginase with IC50 -in range of 1.5-11 µM. Compounds 2 and 5 also showed activity against promastigotes of L. amazonensis with IC50  = 61 (28-133) µM and IC50  = 14 (9-24) µM, respectively. Further computational studies applying molecular docking simulations were performed on the competitive inhibitors to gain insight into the molecular basis for arginase inhibition and could be exploited to the development of new antileishmanials drug targeting parasite arginase.