Sequential nucleophilic aromatic substitutions on cyanuric chloride: synthesis of BODIPY derivatives and mechanistic insights.

Herein we report a study on the sequential substitution of different nucleophiles on cyanuric chloride to obtain potential candidates for metal sensors (5a-c). The set of nucleophiles on the 1,3,5-triazine ring includes a phenolic BODIPY, an aminoalkyl pyridine and aminoalkyl phosphoramidates, each one designed to play a specific role in the final fluoroionophore. Three new triazine triads were synthesized in similar yields: 5a (45%), 5b (43%) and 5c (52%) after a methodical sequential combination of the nucleophiles via thermodependent nucleophilic aromatic substitution of the three chlorine atoms of cyanuric chloride. To ratify the synthetic results we simulated the reaction mechanisms for the different nucleophiles, aiming to address the distinctive orthogonality and temperature control inherent in this process, identifying and providing a sound rationale for any preferential sequence of nucleophiles inserted into the triazine core. According to our experimental and computational analysis (thermo- and kinetic preferences), we have identified the following preferential order for the sequential substitution: p-hydroxybenzaldehyde > 2-(pyridin-2-yl)ethanamine > aminoalkyl phosphoramidate, indicating that all steps follow a single-step process (concerted) in two stages, where nucleophilic addition precedes leaving group dissociation. The Meisenheimer σ-complex was identified as a transition state structure, with insufficient stability to exist as an intermediate. We observed a consistent and progressive increase in barrier height: 2-8 kcal mol-1 for the first step, 9-15 kcal mol-1 for the second step, and >15 kcal mol-1 for the third substitution. These findings align with the experimental observation of thermodependency in the sequential substitution.

Exploring borderline SN1-SN2 mechanisms: the role of explicit solvation protocols in the DFT investigation of isopropyl chloride.

Nucleophilic substitution at saturated carbon is a crucial class of organic reactions, playing a pivotal role in various chemical transformations that yield valuable compounds for society. Despite the well-established SN1 and SN2 mechanisms, secondary substrates, particularly in solvolysis reactions, often exhibit a borderline pathway. A molecular-level understanding of these processes is fundamental for developing more efficient chemical transformations. Typically, quantum-chemical simulations of the solvent medium combine explicit and implicit solvation methods. The configuration of explicit molecules can be defined through top-down approaches, such as Monte Carlo (MC) calculations for generating initial configurations, and bottom-up methods that involve user-dependent protocols to add solvent molecules around the substrate. Herein, we investigated the borderline mechanism of the hydrolysis of a secondary substrate, isopropyl chloride (iPrCl), at DFT-M06-2X/aug-cc-pVDZ level, employing explicit and explicit + implicit protocols. Top-down and bottom-up approaches were employed to generate substrate-solvent complexes of varying number (n = 1, 3, 5, 7, 9, and 12) and configurations of H2O molecules. Our findings consistently reveal that regardless of the solvation approach, the hydrolysis of iPrCl follows a loose-SN2-like mechanism with nucleophilic solvent assistance. Increasing the water cluster around the substrate in most cases led to reaction barriers of ΔH‡ ≈ 21 kcal mol-1, with nine water molecules from MC configurations sufficient to describe the reaction. The More O'Ferrall-Jencks plot demonstrates an SN1-like character for all transition state structures, showing a clear merged profile. The fragmentation activation strain analyses indicate that energy barriers are predominantly controlled by solvent-substrate interactions, supported by the leaving group stabilization assessed through CHELPG atomic charges.

Green Approach for the Synthesis of Chalcogenyl- 2,3-dihydrobenzofuran Derivatives Through Allyl-phenols/ Naphthols and Their Potential as MAO-B Inhibitors.

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

Negative impacts of the administration of hydroxycloroquine and anticoagulant in patients with SARS-COV-2 infection: a randomized clinical trial / Impactos negativos da administração de hidroxicloroquina e anticoagulante em pacientes com infecção por SARS-COV-2: um ensaio clínico randomizado

Purpose: To evaluate antimalarial with or without anticoagulant treatment, in patients with recent SARS-COV-2 infection. Methods: Clinical study carried out at Samuel Libânio Clinic Hospital, University of Vale do Sapucaí, Pouso Alegre-MG. Approved by the Ethics Committee (4.034.077) and registered in the Clinical Trials (NCT04788355). Suspected patients for COVID-19 were included in the emergency room. The groups were: C (control) with 6 patients, A (anticoagulant apixaban) with 9 patients, H (hydroxychloroquine) with 5 patients and HA (hydroxychloroquine and anticoagulant apixaban) with 8 patients. Results: there were no significant differences between groups. The HA group, in which there was an intervention with two drugs, presented a greater number of days with symptoms (p = 0.037) and worse results, when compared to the control: most relevant symptoms, were: cough (p = 0.001), and anosmia / ageusia (p = 0.011) headache (p = 0.001). Conclusion: The present study began when there were doubts about the use of drugs such as Hydroxychloroquine (HCQ) and apixaban (APX). The reduced "n" was defined through bureaucratic and polemic issues independent of the authors' actions. No clinical benefit was associated with HCQ and APX. There was an increase in the number of symptomatic days when HCQ and APX were administered. Despite the limitations, there was no therapeutic indication of the evaluated drugs. [au]

Objetivo: Avaliar antimalárico com ou sem tratamento anticoagulante, em pacientes com infecção recente por SARS-COV-2. Métodos: Estudo clínico realizado no Hospital das Clínicas Samuel Libânio da Universidade do Vale do Sapucaí, Pouso Alegre-MG. Aprovado pelo Comitê de Ética (4.034.077) e registrado nos Ensaios Clínicos (NCT04788355). Pacientes suspeitos de COVID-19 foram incluídos na sala de emergência. Os grupos foram: C (controle) com 6 pacientes, A (anticoagulante apixabana) com 9 pacientes, H (hidroxicloroquina) com 5 pacientes e HA (hidroxicloroquina e anticoagulante apixabana) com 8 pacientes. Resultados: não houve diferenças significativas entre os grupos. O grupo HA, no qual houve intervenção com dois medicamentos, apresentou maior número de dias com sintomas (p = 0,037) e piores resultados, quando comparado ao controle: os sintomas mais relevantes foram: tosse (p = 0,001), e anosmia/ageusia (p = 0,011) cefaléia (p = 0,001). Conclusão: O presente estudo teve início quando havia dúvidas sobre o uso de medicamentos como hidroxicloroquina (HCQ) e apixabana (APX). O "n" reduzido foi definido por meio de questões burocráticas e polêmicas independentes das ações dos autores. Nenhum benefício clínico foi associado com HCQ e APX. Houve um aumento no número de dias sintomáticos quando HCQ e APX foram administrados. Apesar das limitações, não houve indicação terapêutica dos medicamentos avaliados. [au]

Gluten-Free Diet Reduces Diet Quality and Increases Inflammatory Potential in Non-Celiac Healthy Women.

AIM: Gluten-free diets (GFDs) have gained popularity in the general population. Nonetheless, controlled studies are necessary before decisions can be made to promote GFDs. We aimed to evaluate the effects of gluten intake on body weight, body composition, and resting energy expenditure and observe the changes in nutrient intake caused by GFDs. METHODS: Twenty-three women were kept on a GFD for six weeks and received muffins with 20 g of gluten isolate (gluten period) or muffins without gluten (gluten-free period) in a crossover, single-blind, non-randomized trial. Gastrointestinal symptoms, food frequency questionnaires, body composition, and resting energy expenditure were assessed before the study (habitual or usual diet) and in the third and sixth weeks. Food intake was recorded daily for six weeks. RESULTS: Gastrointestinal symptoms, resting energy expenditure, and body weight and composition were similar during the gluten period and gluten-free period. When the diet of the gluten-free period was compared with the habitual diet, we found an increase in the intake of fat and sodium and a reduction in the intake of fiber and vitamins B1, B6, B12, and folate. The nutrient imbalance caused by a GFD led to an increase in the dietary inflammatory index, thus suggesting that this type of diet has high inflammatory potential. CONCLUSION: Gluten intake (20 g/day) did not alter body composition and resting energy expenditure in healthy women without caloric restriction in the diet for a short period (three weeks). However, a GFD led to changes in the composition of the diet, which worsened the quality of the diet and increased its inflammatory potential.

Formation of Dimethyl Carbonate from CO2 and Methanol Catalyzed by Me2SnO: A Density Functional Theory Approach.

The conversion of CO2 into dimethyl carbonate (DMC) is an environmental and industrial appealing topic because it contributes to reduce the emissions of CO2 and to increase its use as raw material. In the present study we employed the CAM-B3LYP/def2-SVP DFT approach to evaluate the thermodynamic and kinetic parameters for the catalytic conversion of CO2 and methanol into DMC. Starting with the activation of four methanol molecules by the [Me2SnO]2 dimer, we computed all the stationary points along the pathway to convert CO2 and methanol into the DMC. The capture of two CO2 molecules is promoted by an alkoxitin intermediate, in an exothermic process, with low activation energy. Formation of a first DMC occurs after an intramolecular rerrangement involving a tetrahedral intermediate. The formation of a second DMC may occur either in a process similar to the first one or by dimerization of the hemicarbonate formed after releasing the first DMC. In this pathway, the [Me2(OH)SnO(OMe)SnMe2]2 complex is formed. This complex is less reactive than [Me2Sn(OMe)2]2 but still conserves the catalytic activity. Identification of this mechanism suggests that the catalytic action of Me2SnO can be improved by modulating the formation of the final [Me2(OH)SnO(OMe)SnMe2]2 complex.

Inconsistent effects of gluten on obesity: is there a role for the haptoglobin isoforms?

BACKGROUND AND AIMS: There is no clear evidence about the effects of gluten intake on obesity. It is known that gluten's effects on gut permeability are mediated by zonulin, a protein identified as pre-haptoglobin 2, a physiological regulator of the intestinal barrier. We investigated the obesogenic and inflammatory effects of gluten and its association with the haptoglobin genotype. METHODS: This was a single blinded, crossover study, including 40 overweight or obesity women free of celiac disease. Participants adopted a gluten-free diet (GFD) for 8 weeks and consumed a gluten-free muffin (GF-M) or a gluten-containing muffin (GLU-M, 24 g gluten) for 4 weeks, switching muffin type during the subsequent 4 weeks. During a follow-up period of 4 weeks we evaluated the usual diet (UD). Food diaries were collected to estimate the macronutrient intake and dietary inflammatory index (DII®). Bodyweight and composition, resting energy expenditure (REE), and cytokines were assessed. Haptoglobin alleles (Hp1 and Hp2) were genotyped to characterize zonulin expression. RESULTS: Energy and macronutrient intakes were similar during both periods, except for protein intake, which was higher during GLU-M. DII scores indicated a more inflammatory profile during the GF-M and GLU-M periods compared to UD. No differences were observed in body composition or REE between interventions when the Hp genotype was not considered. Nonetheless, those carrying the Hp2-2 genotype (overexpressing zonulin) presented lower REE and higher levels of IL6 and IL1beta only during gluten intake (GLU-M and UD) compared to age- and body mass index-matched Hp1-1 carrier. These results suggest an obesogenic and inflammatory action of gluten only in those overexpressing zonulin (Hp2-2). CONCLUSION: These results highlight the importance of zonulin as the mediator of gluten obesogenic and inflammatory effects. Our data suggest that in the presence of gluten, zonulin release is associated with a reduction of REE and an increase of inflammatory markers that are not seen in zonulin low producers.

Novel genetic associations and gene-gene interactions of chemokine receptor and chemokine genetic polymorphisms in HIV/AIDS.

OBJECTIVE: To investigate the influence of candidate polymorphisms on chemokine receptor/ligand genes on HIV infection and AIDS progression (HIV/AIDS). DESIGN: Fifteen polymorphisms of the CCR3, CCR4, CCR5, CCR6, CCR8, CXCR3, CXCR6, CCL20, CCL22 and CXCL10 genes were analysed in 206 HIV-positive patients classified as rapid progressors (n = 40), or nonrapid progressors (n = 166), and in 294 HIV-seronegative patients. METHODS: The polymorphisms were genotyped using minisequencing. Genetic models were tested using binomial logistic regression; nonparametric multifactor dimensionality reduction (MDR) was used to detect gene-gene interactions. RESULTS: The CCR3 rs3091250 [TT, adjusted odds ratio (AOR): 2.147, 95% confidence interval (CI) 1.076-4.287, P = 0.030], CCR8 rs2853699 (GC/CC, AOR: 1.577, 95% CI 1.049-2.371, P = 0.029), CXCL10 rs56061981 (CT/TT, AOR: 1.819, 95% CI 1.074-3.081, P = 0.026) and CCL22 rs4359426 (CA/AA, AOR: 1.887, 95% CI 1.021-3.487, P = 0.043) polymorphisms were associated with susceptibility to HIV infection. The CCL20 rs13034664 (CC, OR: 0.214, 95% CI 0.063-0.730, P = 0.014) and CCL22 rs4359426 (CA/AA, OR: 2.685, 95% CI 1.128-6.392, P = 0.026) variants were associated with rapid progression to AIDS. In MDR analyses revealed that the CXCL10 rs56061981 and CCL22 rs4359426 combination was the best model, with 57% accuracy (P = 0.008) for predicting susceptibility to HIV infection. CONCLUSION: Our results provide new insights into the influence of candidate chemokine receptor/ligand polymorphisms and significant evidence for gene-gene interactions on HIV/AIDS susceptibility.

[Counseling regarding healthy lifestyles in primary healthcare and the dietary practices of clients]. / Aconselhamento sobre modos saudáveis de vida na Atenção Primária e práticas alimentares dos usuários.

This cross-sectional study examines a counseling program on healthy lifestyles run by health care professionals to establish the adoption of healthy dietary practices by patients attending a primary health care unit. Participants in the study included 417 clients of the unit, the majority of whom were women (78.9%), with an average age of 39 years, a high incidence of excessive weight, (59.1%), important dietary inadequacies, and with a contrastingly low frequency of receiving counseling (40.8%). Clients receiving counseling displayed more appropriate consumption of candy/gum (p=0.031), soft drinks (p=0.036), salty foods (p=0.037), artificial flavorings (p=0.005) and eggs (p=0.010). Adoption of healthy dietary practices was more common among older individuals and women (p <0.05). Despite the importance of nutritional counseling in dealing with such health problems, this was not prevalent, suggesting the need for greater intervention by health care professionals aimed at preventing and controlling disease and promoting good health.

Aconselhamento sobre modos saudáveis de vida na Atenção Primária e práticas alimentares dos usuários / Consejos sobre hábitos de vida saludables en la atención básica y prácticas alimentarias de los pacientes / Counseling regarding healthy lifestyles in primary healthcare and the dietary practices of clients

Trata-se de estudo seccional para verificar a realização de aconselhamento sobre modos saudáveis de vida por profissionais de saúde e sua associação com a adoção de práticas alimentares saudáveis em serviço de Atenção Primária à Saúde. Participaram 417 usuários, a maioria mulheres (78,9%), com mediana de idade de 39 anos, elevada prevalência de excesso de peso (59,1%) e inadequações alimentares importantes, contrastando com a baixa frequência de aconselhamento (40,8%). Mas, ainda assim, os usuários aconselhados apresentaram maior adequação no consumo de balas/goma de mascar (p=0,031), refrigerante comum (p=0,036), salgados (p=0,037), temperos industrializados (p=0,005) e ovos (p=0,010). A adoção de práticas alimentares saudáveis foi mais frequente entre os mais velhos e as mulheres (p<0,05). Apesar da importância de aconselhamento frente ao perfil alimentar e de saúde identificado, este foi pouco frequente, sugerindo a necessidade de maior atuação dos profissionais de saúde, visando à prevenção, ao controle de agravos e à promoção da saúde.

This cross-sectional study examines a counseling program on healthy lifestyles run by health care professionals to establish the adoption of healthy dietary practices by patients attending a primary health care unit. Participants in the study included 417 clients of the unit, the majority of whom were women (78.9%), with an average age of 39 years, a high incidence of excessive weight, (59.1%), important dietary inadequacies, and with a contrastingly low frequency of receiving counseling (40.8%). Clients receiving counseling displayed more appropriate consumption of candy/gum (p=0.031), softdrinks (p=0.036), salty foods (p=0.037), artificial flavorings (p=0.005) and eggs (p=0.010). Adoption of healthy dietary practices was more common among older individuals and women (p <0.05). Despite the importance of nutritional counseling in dealing with such health problems, this was not prevalent, suggesting the need for greater intervention by health care professionals aimed at preventing and controlling disease and promoting good health.

Estudio seccional que apunta a verificar la efectivización de consejos sobre hábitos de vida saludables por profesionales de salud y su asociación con la adopción de prácticas alimentarias saludables en Servicio de Atención Básica de Salud. Participaron 417 pacientes, mayoritariamente mujeres (78,9%), con mediana etaria de 39 años, alta prevalencia de exceso de peso (59,1%) y alimentación inadecuada, contrastándose con la baja frecuencia de aconsejado (40,8%). Aún así, los pacientes aconsejados presentaron mayor adecuación en el consumo de caramelos/chicles (p=0,031), refrescos gasificados (p=0,036), pasteles fritos (p=0,037), condimentos industrializados (p=0,005) y huevos (p=0,010). La adopción de prácticas alimentarias saludables fue más frecuente entre los de mayor edad y las mujeres (p<0,05). A pesar de la importancia de aconsejarse en función del perfil alimentario y de salud identificado, éste fue poco frecuente, sugiriéndose la necesidad de mayor actuación profesional, apuntando a prevenir y controlar problemas derivados y a la promoción de salud.