2-Aryladenine Derivatives as a Potent Scaffold for Adenosine Receptor Antagonists: The 6-Morpholino Derivatives.

A set of 2-aryl-9-H or methyl-6-morpholinopurine derivatives were synthesized and assayed through radioligand binding tests at human A1, A2A, A2B, and A3 adenosine receptor subtypes. Eleven purines showed potent antagonism at A1, A3, dual A1/A2A, A1/A2B, or A1/A3 adenosine receptors. Additionally, three compounds showed high affinity without selectivity for any specific adenosine receptor. The structure-activity relationships were made for this group of new compounds. The 9-methylpurine derivatives were generally less potent but more selective, and the 9H-purine derivatives were more potent but less selective. These compounds can be an important source of new biochemical tools and/or pharmacological drugs.

A novel smartphone app for blood pressure measurement: a proof-of-concept study against an arterial catheter.

Smartphones may provide a highly available access to simplified hypertension screening in environments with limited health care resources. Most studies involving smartphone blood pressure (BP) apps have focused on validation in static conditions without taking into account intraindividual BP variations. We report here the first experimental evidence of smartphone-derived BP estimation compared to an arterial catheter in a highly dynamic context such as induction of general anesthesia. We tested a smartphone app (OptiBP) on 121 patients requiring general anesthesia and invasive BP monitoring. For each patient, ten 1-min segments aligned in time with ten smartphone recordings were extracted from the continuous invasive BP. A total of 1152 recordings from 119 patients were analyzed. After exclusion of 2 subjects and rejection of 565 recordings due to BP estimation not generated by the app, we retained 565 recordings from 109 patients (acceptance rate 51.1%). Concordance rate (CR) and angular CR demonstrated values of more than 90% for systolic (SBP), diastolic (DBP) and mean (MBP) BP. Error grid analysis showed that 98% of measurement pairs were in no- or low-risk zones for SBP and MBP, of which more than 89% in the no-risk zone. Evaluation of accuracy and precision [bias ± standard deviation (95% limits of agreement)] between the app and the invasive BP was 0.0 ± 7.5 mmHg [- 14.9, 14.8], 0.1 ± 2.9 mmHg [- 5.5, 5.7], and 0.1 ± 4.2 mmHg [- 8.3, 8.4] for SBP, DBP and MBP respectively. To the best of our knowledge, this is the first time a smartphone app was compared to an invasive BP reference. Its trending ability was investigated in highly dynamic conditions, demonstrating high concordance and accuracy. Our study could lead the way for mobile devices to leverage the measurement of BP and management of hypertension.

2-Aryladenine derivatives as a potent scaffold for A1, A3 and dual A1/A3 adenosine receptor antagonists: Synthesis and structure-activity relationships.

From a collection containing more than 1500 academic compounds, in silico screening identified a hit for the human A1 adenosine receptor containing a new purine scaffold. To study the structure activity relationships of this new chemical series for adenosine receptors, a library of 24 purines was synthesized and tested in radioligand binding assays at human A1, A2A, A2B and A3 adenosine receptor subtypes. Fourteen molecules showed potent antagonism at A1, A3 or dual A1/A3 adenosine receptors. This purine scaffold is an important source for novel biochemical tools and/or therapeutic drugs.

Inhibitory Effect of 5-Aminoimidazole-4-Carbohydrazonamides Derivatives Against Candida spp. Biofilm on Nanohydroxyapatite Substrate.

Candida can adhere and form biofilm on biomaterials commonly used in medical devices which is a key attribute that enhances its ability to cause infections in humans. Furthermore, biomaterial-related infections represent a major therapeutic challenge since Candida biofilms are implicated in antifungal therapies failure. The goals of the present work were to investigate the effect of three 5-aminoimidazole-4-carbohydrazonamides, namely (Z)-5-amino-1-methyl-N'-aryl-1H-imidazole-4-carbohydrazonamides [aryl = phenyl (1a), 4-fluorophenyl (1b), 3-fluorophenyl (1c)], on Candida albicans and Candida krusei biofilm on nanohydroxyapatite substrate, a well-known bioactive ceramic material. To address these goals, both quantitative methods (by cultivable cell numbers) and qualitative evaluation (by scanning electron microscopy) were used. Compounds cytocompatibility towards osteoblast-like cells was also evaluated after 24 h of exposure, through resazurin assay. The three tested compounds displayed a strong inhibitory effect on biofilm development of both Candida species as potent in vitro activity against C. albicans sessile cells. Regarding cytocompatibility, a concentration-dependent effect was observed. Together, these findings indicated that the potent activity of imidazole derivatives on Candida spp. biofilms on nanohydroxyapatite substrate, in particular compound 1c, is worth further investigating.

New Nitrogen Compounds Coupled to Phenolic Units with Antioxidant and Antifungal Activities: Synthesis and Structure⁻Activity Relationship.

A selection of 1-amino-2-arylidenamine-1,2-(dicyano)ethenes 3 was synthesized and cyclized to 2-aryl-4,5-dicyano-1H-imidazoles 4 upon reflux in ethyl acetate/acetonitrile, in the presence of manganese dioxide. These compounds were tested for their antioxidant capacity by cyclic voltammetry, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and deoxyribose degradation assays. The minimum inhibitory concentration of all compounds was evaluated against two yeast species, Saccharomyces cerevisiae and Candida albicans. Their toxicity was tested in mammal fibroblasts. Among the synthesised compounds, two presented dual antioxidant/antifungal activity without toxic effects in fibroblasts. The new compounds synthesized in this work are potential biochemical tools and/or therapeutic drugs.

Tuning the magnetic properties of multisegmented Ni/Cu electrodeposited nanowires with controllable Ni lengths.

The fabrication of segmented Ni/Cu nanowires (NWs), with tunable structural and magnetic properties, is reported. A potentiostatic electrodeposition method with a single electrolytic bath has been used to fabricate multisegmented Ni/Cu NWs inside a highly hexagonally ordered anodic nanoporous alumina membrane, with diameters of 50 nm and Ni segment lengths (L Ni) tuned from 10 nm up to 140 nm. The x-ray diffraction results evidenced a strong dependence of the Ni NWs crystallographic face-centered-cubic (fcc) texture along the [220] direction on the aspect ratio of the NWs. The magnetic behavior of the multisegmented Ni/Cu NW arrays, as a function of the magnetic field and temperature, is also studied and correlated with their structural and morphological properties. Micromagnetic simulations, together with the experimental results, showed a dominant antiferromagnetic coupling between Ni segments along the wire length for small low aspect-ratio magnetic segments. When increasing the Ni segments' length, the magnetic interactions between these along the wire became stronger, favouring a ferromagnetic coupling. The Curie temperature of the NWs was also found to strongly depend on the Ni magnetic segment length. Particularly the Curie temperature was found to be reduced 75 K for the 20 nm Ni segments, following the finite-size scaling relation with ξ 0 = 8.1 Å and γ = 0.48. These results emphasize the advantages of using a template assisted method to electrodeposit multilayer NWs, as it allows an easy tailor of the respective morphological, chemical, structural and magnetic properties.

Tuning the Stoichiometry of Ag2S Thin Films for Resistive Switching Applications.

In this work silver-rich and sulfur-rich silver sulfide (Ag2S) thin films were fabricated using a diversified set of experimental methods, namely ion beam deposition and atmosphere- and solution-based sulfurizations. The composition of the Ag2S thin films was studied using X-ray diffraction, Raman spectroscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. We found that it strongly depends on the fabrication conditions, such as sulfurization time and temperature. These conditions, in turn, affect the electrical characteristics of the thin films, namely the resistivity and resistive switching. We were able to control the Ag2S stoichiometry and infer its dependence on the fabrication parameters for all the followed methods.

A case-control study of CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in colorectal cancer.

Polymorphisms in genes encoding P450 cytochrome enzymes may increase the risk of sporadic colorectal cancer (SCRC). Here we investigated the association between SCRC and CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in a case-control study. Moreover, we sought to determine any possible associations between this disease and the sociodemographic factors. We included 273 individuals (74 patients and 199 controls); the gender, age, tobacco usage, and alcohol consumption of the included subjects, and the clinico-histopathological parameters of the tumors, were analyzed. Molecular analyses were performed using PCR-RFLP. The effect of polymorphisms on SCRC development, and the association between this disease and sociodemographic factors were determined by multiple-logistic regression analyses. The combined genotype was also evaluated. Statistically significant differences between the patients and controls regarding the male gender (odds ratio, OR = 0.19, 95% confidence interval, CI = 0.08-0.46; P ≤ 0.05) and age ≥44 years (median = 44; OR = 96.84, 95%CI = 21.78-430.49; P ≤ 0.05) were observed. The evaluated polymorphisms were not associated with SCRC (PstI-CYP2E1: OR = 0.93, 95%CI = 0.30-2.85; P = 0.897; MspI-CYP1A1: OR = 0.75, 95%CI = 0.35-1.61; P = 0.463); the combined genotypes were not associated with the risk of disease. Thus, individuals aged ≥44 years are more sensitive to SCRC, while men are less susceptible. Additionally, polymorphisms in CYP2E1 (PstI) and CYP1A1 (MspI) were not associated with SCRC in the evaluated Brazilian population.

Changing the way we work: elevating energy expenditure with workstation alternatives.

Emerging evidence supports the feasibility of raising daily energy expenditure (EE) by replacing office work-related sedentary behavior with low-intensity non-exercise physical activity (PA) via workstation alternatives to the traditional office chair and desktop computer-based combinations. The purpose of this review article is to introduce a simple taxonomy to facilitate classification and study of workstation alternatives, catalog the diversity of research undertaken to date related to energy balance, and present and summarize the gaps and opportunities for a research agenda for workstation alternatives moving forward. A PubMed search elicited 57 English language articles published since 2000; additional articles were identified by reviewing reference sections and contacting authors. Selection criteria ultimately focused on use of workstation alternatives during simulated or real work tasks. The EE of sitting on a stability ball or using sit-stand/standing desks is comparable to the traditional seated condition (≅1.2 kcal min(-1)). The treadmill and pedal desks (active workstation alternatives) offer the greatest promise in terms of EE (≅2-4 kcal min(-1)). Sitting on a stability ball or using sit-stand/standing desks does not impair task performance relative to the traditional seated condition. Some evidence of typing impairment is inconsistently reported with active workstation alternatives; the finer motor skills required for mouse-related tasks may be more affected. Little is known about learning or adaptation with practice. Users are generally accepting of workstation alternatives; however, there is evidence of less than optimal use. Active workstations (that is, treadmill desks and pedal desks) in particular represent a potential strategy for mitigating the diminished EE inherent to contemporary office-based workplaces, but only if they are scalable. The science supporting active workstations is young and heterogeneous; however, this means that there are many knowledge gaps and opportunities for research, including those focused on implementation issues related to optimizing both employers' and workers' uptake.

Synthesis and radical scavenging activity of phenol-imidazole conjugates.

Novel hydroxylated benzylideneamino imidazole derivatives were synthesized and their radical scavenging activity was assessed against DPPH and hydroxyl radicals. In the DPPH assay, most of the synthesized compounds showed an IC50 in the range 3.2µM⩽IC50⩽8.4µM, lower than the reference compound trolox (IC50=9.5µM) or the parent aldehydes (5.4µM⩽IC50⩽11.6µM). The activity depends mainly on the phenolic subunit (number and position of the hydroxyl groups) and the extent of conjugation with the imidazole ring. In the deoxyribose assay, all the compounds, including parent imidazoles and aldehydes, showed high activity against the hydroxyl radical and the ability to chelate iron ions. At 5µM concentration, the compounds protected the deoxyribose from degradation by hydroxyl radical between 62% and 38%.

Synthesis and antimicrobial activity of novel 5-aminoimidazole-4-carboxamidrazones.

A mild and simple method was developed to prepare a series of fifteen 5-aminoimidazole 4-carboxamidrazones, starting from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles. The antimicrobial activity of these novel amidrazones was screened against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Pseudomonas aeruginosa) bacteria and Candida sp. (Candida albicans, Candida krusei, Candida parapsilosis). Only a subset of compounds displayed fair-moderate activity against S. aureus and E. coli but all exhibited activity against Candida sp. The three most potent antifungal compounds were further tested against Cryptococcus neoformans, Aspergillus fumigatus and three dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum). These three hit compounds strongly inhibited C. krusei and C. neoformans growth, although their activity on filamentous fungi was very weak when compared to the activity on yeasts.

A simple protocol for the synthesis of perylene bisimides from perylene tetracarboxylic dianhydride.

Perylene bisimides are highly attractive polycyclic aromatic hydrocarbons due to their photostability associated to unique and characteristic photochemical properties. They have been widely used for analytical purposes, despite the hydrophobicity of most of these compounds. The ring substitution pattern plays an important role in fine-tuning the physicochemical properties that govern solubility and aggregation. In this work, a selection of perylene bisimides were prepared from the reaction of perylenetetracarboxylic dianhydride with α-amino acids or primary aliphatic and aromatic amines. These molecules were obtained in good yield by a simple synthetic protocol based on the use of imidazole as a green solvent and avoiding the need for complex purification methods, a major advantage for future applications. Functionalization of the exocyclic substituent can also be performed and was exemplified by the incorporation of the maleimide and anthraquinone moieties.

Discovery of 2,9-diaryl-6-carbamoylpurines as a novel class of antitubercular agents.

A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against Mycobacterium tuberculosis strain H37Rv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve the activity. The most active compound of this set has a phenyl group at N-9 and a 4-hydroxyphenyl group at C-2, displaying an IC90 = 1.2 µg/mL and a selectivity index higher than 25.5. This compound served as a Hit to design the second set of derivatives. A phenyl group at N-9 was maintained, and the group at C-2 was diversified. The SAR analysis showed that the aryl unit at C-2 must have an oxygen or nitrogen atom bonded in the para position. A proton, a small alkyl or a substituted aryl group may also be bonded to the oxygen. The compound with the 4-methoxyphenyl group at C-2, 1Bd, exhibits the highest activity with an IC90 < 0.19 µg/mL. This compound is highly potent against M. tuberculosis strain H37Rv and non-toxic for VERO mammalian cells with an SI > 153.8. Compound 1Bd was also non-cytotoxic against primary macrophage cultures at IC90, 2xIC90, and 10xIC90 and significantly reduced the bacterial load in M. tuberculosis-infected macrophages at the same concentrations. Compound 1Bd showed a favorable pharmacokinetic profile when administered orally, with major lung and liver accumulation. In vivo antimycobacterial efficacy of 1Bd was tested at 25 mg/kg. At the tested regimen, a decrease in bacterial burden was observed in the liver. Optimization of the treatment regimen should be performed to fully potentiate the in vivo efficacy of our lead molecule, particularly in the lung, the main target organ of M. tuberculosis.

Magnetic properties of Co nanopillar arrays prepared from alumina templates.

The preparation of magnetic nanopillars from anodic alumina templates represents a cheap way to obtain extensive ordered arrays, and thus is very appealing for nanotechnology applications. In this paper we report the preparation of arrays of Co nanopillars with 120 nm height and varying diameter. The high anisotropy of Co offers an additional possibility to control their magnetic properties. The magnetic properties of arrays of Co nanopillars are studied both experimentally and by micromagnetic simulations. Experiment and modeling show crucial changes of hysteresis loops when the diameter is increased. Magnetic data are interpreted considering the change of crystalline structure as well as the influence of geometry. The micromagnetic simulations explain the measured magnetic properties by the role of magnetocrystalline anisotropy and the combined influence of the shape anisotropy and the interactions. They also show the change in the reversal mode with the increased diameter from vortex propagation to curling when the field is applied parallel to the nanopillar axis, and from coherent rotation to curling when it is applied perpendicular.

Co nanostructures in ordered templates: comparative FORC analysis.

A comparative study on the structural and magnetic properties of highly ordered hexagonal arrays of Co nanoholes, nanowires, nanopillars and nanotubes, with tuned pore/wire/tube diameters, is here presented. The magnetic interactions and their dependence on the geometric features of the arrays were studied using first-order reversal curves (FORCs). For all nanostructures we observe an increase of the magnetostatic interactions with the templates' pore diameter, with the higher (smaller) values found for the nanowire (nanohole) arrays. For the smallest diameters studied (35 nm), all types of arrays could be considered as almost isolated nanostructures, where local interactions prevail. In particular, both nanotube and nanohole arrays exhibit considerable local magnetostatic interactions coming from the stray fields within each void or empty core. On the other hand, the coercivity is found to decrease with diameter for the elongated nanostructures, while it increases with the pore diameter for the nanohole arrays. This behavior is associated with the magnetization reversal mechanisms present in each array. This work highlights a versatile route to tailor the size, geometrical arrangement and magnetostatic interactions of ordered arrays and demonstrates their importance for the tuning of the magnetic behavior of nanometric devices.

Probing the quality of Ni filled nanoporous alumina templates by magnetic techniques.

Pulsed electrodeposition prepared porous alumina templates with Ni nanowires pore filling ranged from 1 to 100%, depending on the alumina barrier-layer thickness, were probed by continuous wave ferromagnetic resonance at room temperature. For completely filled samples, a single resonance peak was observed in the whole range of angles between the applied magnetic field and normal to the sample plane. Its position was described by Kittel formula that takes into account shape anisotropy of individual Ni wires and dipolar interactions between them. For the samples with lower pore filling the effective anisotropy field decreased and the resonance linewidth in the perpendicular configuration increased. Also a quite intense second peak was observed at lower fields for these samples. These changes are associated with reduction of pore filling percentage that can lead to decrease of dipolar interactions between nanowires and to appearance of magnetic inhomogeneities inside wires.

Regioselective Synthesis of 2-Aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides Self-Assisted by a 2-Hydroxyaryl Group.

The reactivity of the diaminomaleonitrile-based imines containing hydroxyphenyl substituents with diverse aromatic aldehydes has been explored for the synthesis of novel highly substituted nitrogen heterocycles, which are considered privileged scaffolds in drug discovery. We report here a simple and efficient method for the regiocontrolled synthesis of a variety of 2-aryl-5-cyano-1-(2-hydroxyaryl)-1H-imidazole-4-carboxamides from 2-hydroxybenzylidene imines and aromatic aldehydes. Computational studies on the reaction path revealed that the regioselectivity of the reaction toward the formation of imidazole derivatives instead of 1,2-dihydropyrazines, most likely via a diaza-Cope rearrangement, is driven by the 2-hydroxyaryl group in the scaffold. The latter group promotes the intramolecular abstraction and protonation process in the cycloadduct intermediate, triggering the evolution of the reaction toward the formation of imidazole derivatives.

Tunning pore filling of anodic alumina templates by accurate control of the bottom barrier layer thickness.

The role of the alumina barrier layer thickness (δ(b)) on the growth of Ni nanowires (NWs) in porous anodic alumina (PAA) has been revealed. By varying the final anodization voltage to form dendrites at the bottom of the nanoporous structure, we are able to optimize δ(b) (in the 2-16 nm range), allowing us to obtain a Ni pore filling percentage (f(p)) of almost 100% for δ(b) = 10 nm. However, deviations from this optimal δ(b)-value led to a strong decrease of f(p). Moreover, an increase of the electrodeposition efficiency (EE) and NW homogeneity was also verified for δ(b) up to 10 nm. Such increase in nominal δ(b) leads to a consistent growth rate in all pores and consequently a complete and uniform nanopore filling. On the other hand, the decrease in electrodeposition efficiency visible for δ(b) > 10 nm is related with hydrogen evolution and dielectric breakdown of the insulator layer due to the required high deposition voltages. Non-uniform NW growth is then visible, with the consequent decrease in f(p). The control of the pore filling and length homogeneity of the fabricated 1D metallic nanostructures, combined with the ability to adjust the pore dimensions of PAA, can bring novel approaches for the fabrication of nano-objects and thus exciting new applications.

Unzipping of functionalized multiwall carbon nanotubes induced by STM.

Carbon nanotubes (CNTs), functionalized by a cycloaddition reaction, were studied by ultrahigh vacuum scanning tunneling microscopy (STM). The STM images provided evidence for partial or total unzipping of the outer CNT layer. The formation of graphene ribbons was triggered by the STM tip, under specific operating conditions. A model for the unzipping is proposed, based on the perturbation of the pi-conjugation along the CNT surface induced by the cycloaddition reaction.

In silico directed chemical probing of the adenosine receptor family.

One of the grand challenges in chemical biology is identifying a small-molecule modulator for each individual function of all human proteins. Instead of targeting one protein at a time, an efficient approach to address this challenge is to target entire protein families by taking advantage of the relatively high levels of chemical promiscuity observed within certain boundaries of sequence phylogeny. We recently developed a computational approach to identifying the potential protein targets of compounds based on their similarity to known bioactive molecules for almost 700 targets. Here, we describe the direct identification of novel antagonists for all four adenosine receptor subtypes by applying our virtual profiling approach to a unique synthesis-driven chemical collection composed of 482 biologically-orphan molecules. These results illustrate the potential role of in silico target profiling to guide efficiently screening campaigns directed to discover new chemical probes for all members of a protein family.