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In this study, a novel 3,3'-bipyrazolo [3,4-b]pyridine-type structure was synthesized from 5-acetylamino-3-methyl-1-phenylpyrazole using the Vilsmeier-Haack reaction as a key step. The spectroscopic properties and structural elucidation of the compound were determined with the use of FT-IR, HRMS, 1H NMR, and 13C NMR. Likewise, the theoretical analysis of the IR and NMR spectra allowed peaks to be assigned and a solid correlation was demonstrated between the experimental and theoretical results. Finally, ab initio calculations based on the density functional theory method at the B3LYP/6-311G (d,p) level of theory were used to determine the conformational energy barrier, facilitating the identification of the most probable conformers of the synthesized compound. Overall, our findings contribute to the understanding of bipyrazolo [3,4-b]pyridine derivatives.

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Abstract Objective: To describe the experience of the insertion of the duodenal stent in patients with malignant obstruction of the gastric outflow tract in a third-level reference center in Cundinamarca. Materials and methods: Observational study, case series. Patients with Malignant gastric outlet obstruction (MGOO) diagnosed between December 2019 and February 2022 underwent the insertion of a self-expanding duodenal metal stent in the Gastroenterology unit of Hospital Universitario de la Samaritana. Results: 17 patients were enrolled, 76% of whom were male, with a mean age of 69 years (standard deviation [SD]: 11 years). Histology confirmed gastric adenocarcinoma was found in 82% of the patients, and 41% reported peritoneal carcinomatosis. We achieved total technical success (100%) and clinical success (88%) (15 patients). Regarding the size of the stent used, 35% (6 patients) were 12 cm, 53% (9 patients) were 9 cm, and 12% (2 patients) were 6 cm. Fluoroscopic and endoscopic guidance was used in 88% of cases. Patient survival at follow-up was an average of 84 days (2.8 months; range: 0-414 days) and currently, 1 patient continues in post-insertion surveillance for stent at the time described in the study. Conclusion: Duodenal stent is an effective and safe palliative management alternative in patients with MGOO that improves symptoms, particularly, oral tolerance and early hospital discharge in this group of patients (with advanced terminal neoplastic disease in the palliative management phase), reducing the need for surgical management.

Resumen Objetivo: Describir la experiencia de la inserción del stent duodenal en pacientes con obstrucción maligna del tracto de salida gástrico en un centro de referencia de tercer nivel de Cundinamarca. Materiales y métodos: Estudio observacional, serie de casos. Pacientes con obstrucción maligna del tracto de salida gástrico (OTSG) diagnosticados entre diciembre de 2019 y febrero de 2022 llevados a inserción de stent metálico autoexpandible duodenal en la unidad de Gastroenterología del Hospital Universitario de la Samaritana. Resultados: 17 pacientes fueron incluidos, de los cuales el 76 % eran hombres, con una edad promedio de 69 años (desviación estándar [DE]: 11 años). Se encontró adenocarcinoma gástrico confirmado por histología en el 82 % de los pacientes, y el 41 % tenía carcinomatosis peritoneal. El éxito técnico fue del 100 % y el éxito clínico fue del 88 % (15 pacientes). En cuanto al tamaño del stent utilizado, el 35 % (6 pacientes) fue de 12 cm, el 53 % (9 pacientes) de 9 cm y el 12 % (2 pacientes) de 6 cm. Se utilizó guía fluoroscópica y endoscópica en el 88 % de los casos. La sobrevida de los pacientes en el seguimiento fue en promedio de 84 días (2,8 meses; rango: 0-414 días) y actualmente 1 paciente continúa en vigilancia posterior a la inserción de stent en el tiempo descrito del estudio. Conclusión: El stent duodenal es una alternativa de manejo paliativo efectiva y segura en los pacientes con OTSG que permite mejorar los síntomas y, en especial, la tolerancia a la vía oral y el egreso hospitalario temprano en este grupo de pacientes con una enfermedad neoplásica avanzada terminal en fase de manejo paliativo, lo que disminuye la necesidad de manejo quirúrgico.

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People spend most of their time indoors, especially during the coronavirus disease. Prolonged exposure to heavy metal-contaminated dust can be harmful to human health. The objectives of this study were to identify the contamination level in outdoor and indoor dust, compare contamination in both environments, and assess the human health risk. Two-hundred thirty-nine samples of dust were taken by Mexico City citizens in 38 homes on the weekends of May 2020. Heavy metal concentrations were measured through XRF. The contamination level was set using the contamination factor with a local and global background value, mixed linear models were used to identify indoor and outdoor differences, and USEPA human health risk methodology was used. Pb, Zn, and Cu had the highest contamination levels, followed by Sr and Mn, using both the local and global background values. The Pb, Zn, and Cu contamination was greater indoors, while higher Mn, Sr, and Fe were detected outdoors. According to the outdoor/indoor ratios, the main sources of Ca, Pb, Zn, and Cu must be indoors, while the main sources of Fe, Mn, Sr, Y, and Ti are outdoors. A human health risk was not detected, as the hazard index was lower than one. However, ailments can be developed due to exposure to Pb, Mn, and Fe in children (hazard index > 0.1). A higher risk due to Pb exposition was found indoors. Indoor environments in Mexico City were more contaminated by heavy metals and represented a higher risk to human health than outdoors during the pandemic isolation.

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Multicomponent reactions were performed to develop novel α,ß-unsaturated carbonyl depsipeptides and peptoids incorporating various chromophores such as cinnamic, coumarin, and quinolines. Thus, through the Passerini and Ugi multicomponent reactions (P-3CR and U-4CR), we obtained thirteen depsipeptides and peptoids in moderate to high yield following the established protocol and fundamentally varying the electron-rich carboxylic acid as reactants. UV/Vis spectroscopy was utilized to study the photophysical properties of the newly synthesized compounds. Differences between the carbonyl-substituted chromophores cause differences in electron delocalization that can be captured in the spectra. The near UV regions of all the compounds exhibited strong absorption bands. Compounds P2, P5, U2, U5, and U7 displayed absorption bands in the range of 250-350 nm, absorbing radiation in this broad region of the electromagnetic spectrum. A photostability study for U5 showed that its molecular structure does not change after exposure to UV radiation. Fluorescence analysis showed an incipient emission of U5, while U6 showed blue fluorescence under UV radiation. The photophysical properties and electronic structure were also determined by TD-DFT theoretical study.

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NADPH oxidase (NOX2) is responsible for reactive oxygen species (ROS) production in neutrophils and has been recognized as a key mediator in inflammatory and cardiovascular pathologies. Nevertheless, there is a lack of specific NOX2 pharmacological inhibitors. In medicinal chemistry, heterocyclic compounds are essential scaffolds for drug design, and among them, indole is a very versatile pharmacophore. We tested the hypothesis that indole heteroaryl-acrylonitrile derivatives may serve as NOX2 inhibitors by evaluating the capacity of 19 of these molecules to inhibit NOX2-derived ROS production in human neutrophils (HL-60 cells). Of these compounds, C6 and C14 exhibited concentration-dependent inhibition of NOX2 (IC50~1 µM). These molecules also reduced NOX2-derived oxidative stress in cardiomyocytes and prevented cardiac damage induced by ischemia-reperfusion. Compound C6 significantly reduced the membrane translocation of p47phox, a cytosolic subunit that is required for NOX2 activation. Molecular docking analyses of the binding modes of these molecules with p47phox indicated that C6 and C14 interact with specific residues in the inner part of the groove of p47phox, the binding cavity for p22phox. This combination of methods showed that novel indole heteroaryl acrylonitriles represent interesting lead compounds for developing specific and potent NOX2 inhibitors.

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This research aimed to identify the phenolic profile and composition of the aerial parts of three native species used in traditional medicine in the Andean Altiplano of northern Chile: Clinopodium gilliesii (Benth.) Kuntze [Lamiaceae] (commonly known as Muña-Muña), Mutisia acuminata Ruiz & Pav. var. hirsuta (Meyen) Cabrera [Asteraceae] (commonly known as Chinchircoma), and Tagetes multiflora (Kunth), [Asteraceae] (commonly known as Gracilis), as well as to evaluate their potential inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Polyphenolic enriched-extracts (PEEs) of the species were prepared and analyzed and the main components were quantified using HPLC-DAD. In total, 30 phenolic compounds were identified and quantified in all species, including simple phenolics, hydroxycinnamic acids, flavan-3-ols (monomers and polymers), flavanones, and flavonols. In addition, other main phenolics from the extracts were tentatively identified by ESI-MS-MS high-resolution analysis. T. multiflora extract showed the greatest anti-AChE and BChE activity in comparison with C. gilliesii and M. acuminata extracts, being the anti-AChE and BChE activity weak in all extracts in comparison to galantamine control. To comprise to better understand the interactions between cholinesterase enzymes and the main phenolics identified in T. multiflora, molecular docking analysis was conducted.

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Chemical structures of selective blockers of TASK channels contain aromatic groups and amide bonds. Using this rationale, we designed and synthesized a series of compounds based on 3-benzamidobenzoic acid. These compounds block TASK-1 channels by binding to the central cavity. The most active compound is 3-benzoylamino-N-(2-ethyl-phenyl)-benzamide or F3, blocking TASK-1 with an IC50 of 148 nM, showing a reduced inhibition of TASK-3 channels and not a significant effect on different K+ channels. We identified putative F3-binding sites in the TASK-1 channel by molecular modeling studies. Mutation of seven residues to A (I118A, L122A, F125A, Q126A, L232A, I235A, and L239A) markedly decreased the F3-induced inhibition of TASK-1 channels, consistent with the molecular modeling predictions. F3 blocks cell proliferation and viability in the MCF-7 cancer cell line but not in TASK-1 knockdown MCF-7 cells, indicating that it is acting in TASK-1 channels. These results indicated that TASK-1 is necessary to drive proliferation in the MCF-7 cancer cell line.

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In order to find molecules of natural origin with potential biological activities, we isolate and synthesise compounds with agarofuran skeletons (epoxyeudesmanes). From the seeds of Maytenus disticha and Maytenus magellanica we obtained six dihydro-ß-agarofurans, and by means of the Robinson annulation reaction we synthesised five compounds with the same skeleton. The structures were established on the basis of NMR, IR, and MS. The evaluated compounds showed inhibitory activity on the acetylcholinesterase enzyme and on the COX enzymes. Compound 4 emerged as the most potent in the acetylcholinesterase inhibition assay with IC50 17.0 ± 0.016 µM on acetylcholinesterase (AChE). The compounds evaluated were shown to be selective for AChE. The molecular docking, and the propidium displacement assay suggested that the compounds do not bind to the active site of the enzyme AChE, but rather bind to the peripheral anionic site (PAS) of the enzyme, on the other hand, the natural compound 8, showed the best inhibitory activity on the COX-2 enzyme with an IC50 value of 0.04 ± 0.007 µM. The pharmacokinetic profile calculated in silico using the SWISSADME platform shows that these molecules could be considered as potential drugs for the treatment of neurodegenerative diseases such as AD.

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Alzheimer's disease (AD) is a degenerative neurological disease characterized by gradual loss of cognitive skills and memory. The exact pathogenesis involved still remains unrevealed, but several studies indicate the involvement of an array of different enzymes, underlining the multifactorial character of the disease. Inhibition of these enzymes is therefore a powerful approach in the development of AD treatments, with promising candidates, including acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidase. Interestingly, AChE is the target of a major pesticide family (organophosphates), with several reports indicating an intersection between the pesticide's activity and AD. In this study, various TADDOL derivatives were synthesized and their in vitro activities as AChE/BuChE inhibitors as well as their antioxidant activities were studied. Molecular modeling studies revealed the capability of TADDOL derivatives to bind to AChE and induce inhibition, especially compounds 2b and 3c furnishing IC50 values of 36.78 ± 8.97 and 59.23 ± 5.31 µM, respectively. Experimental biological activities and molecular modeling studies clearly demonstrate that TADDOL derivatives with specific stereochemistry have an interesting potential for the design of potent AChE inhibitors. The encouraging results for compounds 2b and 3c indicate them as promising scaffolds for selective and potent AChE inhibitors.

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BACKGROUND: Adenosine is a natural nucleoside present in a variety of organs and tissues, where it acts as a modulator of diverse physiological and pathophysiological processes. These actions are mediated by at least four G protein-coupled receptors, which are widely and differentially expressed in tissues. Interestingly, high concentrations of adenosine have been reported in a variety of tumors. In this context, the final output of adenosine in tumorigenesis will likely depend on the constellation of adenosine receptors expressed by tumor and stromal cells. Notably, activation of the A3 receptor can reduce the proliferative capacity of various cancer cells. OBJECTIVE: This study aimed to describe the anti-proliferative effects of two previously synthesized adenosine derivatives with A3 agonist action (compounds 2b and 2f) through in vitro assays. METHODS: We used gastric and breast cancer cell lines expressing the A3 receptor as in vitro models and theoretical experiments for molecular dynamics and determination of ADME properties. RESULTS: The antiproliferative effects of adenosine derivatives (after determining IC50 values) were comparable or even higher than those described for IB-MECA, a commercially available A3 agonist. Among possible mechanisms involved, apoptosis was found to be induced in MCF-7 cells but not in AGS or MDA-MB-231 cells. Surprisingly, we were unable to observe cellular senescence induction upon treatment with compounds 2b and 2f in any of the cell lines studied, although we cannot rule out other forms of cell cycles exit at this point. CONCLUSION: Both adenosine derivatives showed antiproliferative effects on gastric and breast cancer cell lines, and were able to induce apoptosis, at least in the MCF-7 cell line. Further studies will be necessary to unveil receptor specificity and mechanisms accounting for the antiproliferative properties of these novel semi-synthetic compounds.

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A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of all compounds was tested. Enzyme inhibition assays showed that some hybrids exhibited significant potency to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Especially, the hybrid compound 5n presented the more effective inhibition against AChE (4.24 µM) with an acceptable selectivity index versus BChE (SI: 5.19), while compound 6aa exhibited the greatest inhibition activity on BChE (3.97 µM) and a significant selectivity index against AChE (SI: 0.04). Kinetic studies were carried out for compounds with greater inhibitory activity of cholinesterases. Structure-activity relationships of the molecular hybrids were analyzed, through computational models using a molecular cross-docking algorithm and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy approach, which indicated a good correlation between the experimental inhibition values and the predicted free binding energy.

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Abstract Different studies with university students show the presence of a negative image about the elderly and an absence of positive stereotypes regarding this age group. With the increase of the older population, these stereotypes must disappear in order to work with aged people without a negative view of them. The aim of this paper was to identify the existence of negative stereotypes towards old age in students who are pursuing health-related and not related university degree courses. A total of 262 students were assessed with the CENVE questionnaire. In order to find out whether there were differences between students with respect to negative stereotypes, an ANOVA and a post-hoc comparison test were carried out. Results were significant at the 5% level. These show evidence of the existence of negative stereotypes about old age in students pursuing university degrees related and not related to the field of health. ANOVAs showed differences in total CENVE (F3 259 = 3.574; p = 0.015; r2 = 0.040), Social Motivation dimension (F3259 = 3.697; p = 0.012; rf = 0.042), and Personality dimension (F3259 = 5.157; p = 0.002; r2 = 0.057). The post-hoc tests show the existence of differences in stereotypes depending on the course that is being studied, where the health related courses show the lower level of negative stereotypes.

Resumo Diversos estudos sobre estereótipos com estudantes universitários mostram que as pessoas idosas são percebidas mais frequentemente a partir de uma imagem negativa do que com estereótipos positivos. Levando em consideração o crescente aumento da população idosa na atualidade e como o fim de trabalhar com pessoas mais velhas a partir de uma visão positiva de si mesmos, é preciso que esses estereótipos desapareçam. O objetivo deste trabalho foi determinar se existem estereótipos negativos com respeito à velhice em estudantes de cursos universitários relacionados e não relacionados com o campo da saúde. No total, 262 estudantes foram avaliados com o questionário CENVE e, para saber se existiam diferenças de estereótipos negativos entre os estudantes de acordo com sua habilitação, foi realizada uma análise ANOVA, além de comparações post hoc. Os resultados foram significativos com um nível de 5% e evidenciaram a existência de estereótipos negativos com respeito à velhice em estudantes de habilitações universitárias relacionadas e não relacionadas com o campo da saúde. Os ANOVA mostraram diferenças para o CENVE total (F3259 = 3.574; p = .015; n2 = .040), para a dimensão de motivação social (F3259 = 3.697; p = .012; n2 = .042) e para a dimensão de personalidade (F3259 = 5.157; p = .002; n2 = .057). As provas post hoc mostraram a existência de diferenças no grau de estereótipos negativos de acordo com as habilitações em curso, sendo que as habilitações de saúde mostraram menor grau em comparação com as demais.

Resumen Diversos estudios sobre estereotipos con estudiantes universitarios muestran que las personas mayores son percibidas más desde una imagen negativa que con estereotipos positivos. Teniendo en cuenta el creciente aumento de la población mayor en la actualidad, y con el fin de trabajar con personas mayores desde una visión positiva de sí mismos, es necesario que estos estereotipos desaparezcan. El objetivo de este trabajo fue determinar si existen estereotipos negativos hacia la vejez en estudiantes de carreras universitarias relacionadas y no relacionadas con el campo de la salud. En total, se evaluó a 262 estudiantes con el cuestionario CENVE, y, para saber si existían diferencias de estereotipos negativos entre los estudiantes según su titulación, se realizó un análisis ANOVA, además de comparaciones post hoc. Los resultados fueron significativos al nivel del 5 % y evidenciaron la existencia de estereotipos negativos hacia la vejez en estudiantes de títulos universitarios relacionados y no relacionados con el campo de la salud. Los ANOVA mostraron diferencias para el CENVE total (F3259 = 3.574; p = .015; η 2 = .040), para la dimensión de motivación social (F3259 = 3.697; p = .012; η2 = .042) y para la dimensión de personalidad (F3259 = 5.157; p = .002; η 2 = .057). Las pruebas post hoc mostraron la existencia de diferencias en el grado de estereotipos negativos según las titulaciones en curso, donde las titulaciones sanitarias mostraron menor grado en comparación con las demás.

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In this work, we present results about the synthesis and the antioxidant properties of seven adenosine derivatives. Four of these compounds were synthesized by substituting the N6-position of adenosine with aliphatic amines, and three were obtained by modification of the ribose ring. All compounds were obtained in pure form using column chromatography, and their structures were elucidated by infrared spectroscopy (IR) and Nuclear Magnetic Resonance (NMR). All adenosine derivatives were further evaluated in vitro as free radical scavengers. Our results show that compounds 1c, 3, and 5 display a potent antioxidant effect compared with the reference compound ascorbic acid. In addition, the absorption, distribution, metabolism and excretion (ADME) calculations show favorable pharmacokinetic parameters for the set of compounds analyzed, which guarantees their suitability as potential antioxidant drugs. Furthermore, theoretical analyses using Molecular Quantum Similarity and reactivity indices were performed in order to discriminate the different reactive sites involved in oxidative processes.

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New N-propargyl tetrahydroquinolines 6a-g have been synthesized efficiently through the cationic Povarov reaction (a domino Mannich/Friedel-Crafts reaction), catalyzed by Indium (III) chloride (InCl3), from the corresponding N-propargylanilines preformed, formaldehyde and N-vinylformamide, with good to moderate yields. All tetrahydroquinoline derivatives obtained were evaluated in vitro as free radical scavengers. Results showed that compound 6c presents a potent antioxidant effect compared with ascorbic acid, used as a reference compound. ADME predictions also revealed favorable pharmacokinetic parameters for the synthesized compounds, which warrant their suitability as potentials antioxidant. Additionally, a theoretical study using Molecular Quantum Similarity and reactivity indices were developed to discriminate different reactive sites in the new molecules in which the oxidative process occurs.

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The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20-89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method.

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In recent years, the design, development, and evaluation of several inhibitors of the BACE1 enzyme, as part of Alzheimer's treatment, have gathered the scientific community's interest. Here, a linear regression model was built using binding free energy calculations through the Bennett acceptance ratio method for 20 known inhibitors of the BACE1 enzyme, with a Pearson coefficient of R = 0.88 and R2  = 0.78. The validation of this model was verified employing eight additional random inhibitors, which also gave a linear correlation with R = 0.97 and R2  = 0.93. Furthermore, this linear regression model was also used for proposing the structure of four potential BACE1 inhibitors, and the most active of them gave a theoretical Kd  = 10 nM. However, these molecules have not been synthesized yet. Our team used a total time of more than 800 ns for the Molecular Dynamics to carry out this study, and all the software used were freely available.

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Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities.

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Keeping in mind the concept of green chemistry, this research aims to synthesize and characterize new ionic liquids (ILs) derived from N-cinnamyl imidazole with different sizes of alkyl chains (1, 6, 8, and 10 carbon atoms), and evaluate their antibacterial activity against Skin and soft tissue infections (SSTIs) causative bacteria. The antibacterial screening was carried out by agar well diffusion and the Minimum Inhibitory Concentration (MIC) and Half Maximum Inhibitory Concentration (IC50) of the different ILs were determined by microdilution in broth, also Molecular dynamics simulations were performed to study the interaction mechanism between ILs and membranes. The MIC value in Gram-positive bacteria showed that as the hydrocarbon chain increases, the MIC value decreases with a dose-dependent effect. Furthermore, Gram-negative bacteria showed high MIC values, which were also evidenced in the antibacterial screening. The molecular dynamics showed an incorporation of the ILs with the longer chain (10 C), corresponding to a passive diffusion towards the membrane surface, for its part, the ILs with the shorter chain due to its lack of hydrophobicity was not incorporated into the bilayer. Finally, the new ILs synthesized could be an alternative for the treatment of Gram-positive bacteria causative of SSTIs.

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Since 1929, several researchers have conducted studies in relation to the nucleoside of adenosine (1) mainly distribution identifying, characterizing their biological importance and synthetic chemistry to which this type of molecule has been subjected to obtain multiple of its derivatives. The receptors that interact with adenosine and its derivatives, called purinergic receptors, are classified as A1, A2A, A2B and A3. In the presence of agonists and antagonists, these receptors are involved in various physiological processes and diseases. This review describes and compares some of the synthetic methods that have been developed over the last 30 years for obtaining some adenosine derivatives, classified according to substitution processes, complexation, mating and conjugation. Finally, we mention that although the concentrations of these nucleosides are low in normal tissues, they can increase rapidly in pathophysiological conditions such as hypoxia, ischemia, inflammation, trauma and cancer. In particular, the evaluation of adenosine derivatives as adjunctive therapy promises to have a significant impact on the treatment of certain cancers, although the transfer of these results to clinical practice requires a deeper understanding of how adenosine regulates the process of tumorigenesis.

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Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds, thereby improving their biological applications. In this paper, we report the design and eco-friendly two-step synthesis of novel, fused spiro-pyrazolo[1,5-c]quinazoline derivatives as cholinesterase inhibitors. In addition, we studied their protein-ligand interactions via molecular docking and MM/GBSA calculations for a further rational design of more potent inhibitors. In first step, 2-(1H-pyrazol-5-yl)anilines were obtained through microwave (MW) assisted solvent-free/catalyst-free conditions and the second step involved the synthesis of the spiro-pyrazolo[1,5-c]quinazolines by a cyclocondensation reaction between 2-(1H-pyrazol-5-yl)anilines and cyclic ketones, or acetophenones, using stirring at room temperature. The compounds were obtained in high purity, good yields (50-97%), and at varying reaction times. The spiro-compounds were evaluated as acetylcholinesterase and butyrylcholinesterase inhibitors (AChEIs/BuChEIs) respectively, and the most potent compound exhibited a moderate AChE inhibitory activity (5f: IC50 = 84 µM). Molecular docking studies indicated that the binding mode of the compound 5f share common characteristics with the galantamine/donepezil-AChE complexes. Moreover, free binding energy (ΔG) calculations showed a good agreement with the experimental biological activity values. Our theoretical results indicated that halogen bond interactions could be involved with differential potency of these compounds and provide a new starting point to design novel pyrazolo[1,5-c]quinazolines as new anti-Alzheimer agents.

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