Structure and Ligand Based Virtual Screening and MPO Topological Analysis of Triazolo Thiadiazepine-fused Coumarin Derivatives as Anti-Parkinson Drug Candidates.

Parkinson's disease (PD) is a debilitating condition that can cause locomotor problems in affected patients, such as tremors and body rigidity. PD therapy often includes the use of monoamine oxidase B (MAOB) inhibitors, particularly phenylhalogen compounds and coumarin-based semi-synthetic compounds. The objective of this study was to analyze the structural, pharmacokinetic, and pharmacodynamic profile of a series of Triazolo Thiadiazepine-fused Coumarin Derivatives (TDCDs) against MAOB, in comparison with the inhibitor safinamide. To achieve this goal, we utilized structure-based virtual screening techniques, including target prediction and absorption, distribution, metabolism, and excretion (ADME) prediction based on multi-parameter optimization (MPO) topological analysis, as well as ligand-based virtual screening techniques, such as docking and molecular dynamics. The findings indicate that the TDCDs exhibit structural similarity to other bioactive compounds containing coumarin and MAOB-binding azoles, which are present in the ChEMBL database. The topological analyses suggest that TDCD3 has the best ADME profile, particularly due to the alignment between low lipophilicity and high polarity. The coumarin and triazole portions make a strong contribution to this profile, resulting in a permeability with Papp estimated at 2.15 × 10-5 cm/s, indicating high cell viability. The substance is predicted to be metabolically stable. It is important to note that this is an objective evaluation based on the available data. Molecular docking simulations showed that the ligand has an affinity energy of - 8.075 kcal/mol with MAOB and interacts with biological substrate residues such as Pro102 and Phe103. The results suggest that the compound has a safe profile in relation to the MAOB model, making it a promising active ingredient for the treatment of PD.

Insights of potential trypanocidal effect of the synthetic derivative (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one: in vitro assay, MEV analysis, quantum study, molecular docking, molecular dynamics, MPO analysis, and predictive ADMET.

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.

Analysis of temperature effect in the CO2 absorption using a deep eutectic solvent: An in silico approach.

The excess level of carbon dioxide in the atmosphere has contributed a lot to global warming, occasioning several damages to the planet. Therefore, it is urgent to find ways to capture this gas. Then, the present work analyzed the temperature effect in CO2 absorption through deep eutectic solvents (DESs) based on urea and choline chloride using an in silico approach. The Molecular Dynamics (MD) simulations indicated that the increased temperature reduced the interaction potential of carbon dioxide molecules with the DESs components, indicating that the absorption process is more favorable at 303 K. On the other hand, the Noncovalent Interactions (NCI) simulations suggest that the increased temperature reduced the strong attractions and increased repulsive interactions between the carbon dioxide molecules with the solvent analyzed. Therefore, both in silico approaches suggest that the carbon dioxide absorption is more indicated at 303 K.

Modifiable behavioral risk factors for NCDs and sleep in Brazilian adolescents.

OBJECTIVE: To analyze the association between modifiable behavioral risk factors for non-communicable diseases and sleep parameters in Brazilian adolescents. METHODS: This was a cross-sectional study that used data from the RPS Cohort Consortium, São Luís, Brazil for the follow-up of adolescents aged 18-19 years (n = 2,515). The outcomes were excessive daytime sleepiness (Epworth Sleepiness Scale - ESS) and sleep quality (Pittsburgh Sleep Quality Index - PSQI). The exposures of interest were the behavioral risk factors for non-communicable diseases (NCDs): screen time, physical inactivity, alcohol, smoking, illicit drugs, caffeine intake, and consumption of sugar-sweetened beverages. Excess weight was considered a possible mediator of this association between the exposures of interest and the outcomes. The models were analyzed by modeling with structural equations. RESULTS: Physical inactivity (standardized coefficient, SC = 0.112; p = 0.001), higher consumption of alcohol (SC = 0.168; p = 0.019) and of sugar-sweetened beverages (SC = 0.128; p < 0.001) were associated with excessive daytime sleepiness in adolescents; better socioeconomic status was also associated with this outcome (SC = 0.128; p < 0.001). Physical inactivity (SC = 0.147; p < 0.001) and higher consumption of sugar-sweetened beverages (SC = 0.089; p = 0.003) were also associated with poor sleep quality. Overweight was neither a mediator nor associated with sleep quality or excessive daytime sleepiness. CONCLUSIONS: The main modifiable behavioral risk factors for NCDs are associated with worse sleep parameters already in adolescence, which serves as a warning toward the accumulation of risks for sleep disorders in the future.

A mechanistic insight for the biosynthesis of N,N-dimethyltryptamine: An ONIOM theoretical approach.

Psychoactive natural products are potent serotonergic agonists capable of modulating brain functions such as memory and cognition. These substances have shown therapeutic potential for treating various mental disorders. The fact that N,N-dimethyltryptamine (DMT) is produced endogenously in several plants and animals, including humans, makes it particularly attractive. As an amino acid-derived alkaloid, the DMT biosynthetic pathway is part of the L-tryptophan biochemical cascade and can be divided into the decarboxylation by an aromatic L-amino acid decarboxylase (AADC) for tryptamine formation and the subsequent double-methylation by the indolethylamine-N-methyltransferase (INMT) through the cofactor S-adenosyl-L-methionine (SAM), a methyl donor. Unlike the decarboxylation mechanism of L-tryptophan, the molecular details of the double methylation of tryptamine have not been elucidated. Therefore, we propose an in silico model using molecular dynamics (MD), non-covalent interaction index (NCI) and density functional theory (DFT) calculations with the ONIOM QM:MM B3LYP/6-31+G(d,p):MM/UFF level of theory. Based on the obtained energetic data, the potential energy surface (PES) indicates an SN2 mechanism profile, with the second methylation energy barrier being the rate-limiting step with δG‡=60kJ∙mol-1 larger than the previous methylation, following the NCI analysis showing more repulsive interactions for the second transition state. In addition, the hybridization information of each reaction step provides geometric details about the double-methylation.

De novo design of bioactive phenol and chromone derivatives for inhibitors of Spike glycoprotein of SARS-CoV-2 in silico.

This work presents the synthesis of 12 phenol and chromone derivatives, prepared by the analogs, and the possibility of conducting an in silico study of its derivatives as a therapeutic alternative to combat the SARS-CoV-2, pathogen responsible for COVID-19 pandemic, using its S-glycoprotein as a macromolecular target. After the initial screening for the ranking of the products, it was chosen which structure presented the best energy bond with the target. As a result, derivative 4 was submitted to a molecular growth study using artificial intelligence, where 8436 initial structures were obtained that passed through the interaction filters and similarity to the active glycoprotein pocket through the MolAICal computational package. Thus, 557 Hits with active configuration were generated, which is very promising compared to the BLA reference link for inhibiting the biological target. Molecular dynamics also simulated these compounds to verify their stability within the active protein site to seek new therapeutic propositions to fight against the pandemic. The Hit 48 and 250 are the most active compounds against SARS-CoV-2. In summary, the results show that the Hit 250 would be more active than the natural compound, which could be further developed for further testing against SARS-CoV-2. The study employs the de novo approach to design new drugs, combining artificial intelligence and molecular dynamics simulations to create efficient molecular structures. This research aims to contribute to the development of effective therapeutic strategies against the pandemic.

Sulfonamide derived from anacardic acid as potential antichagasic: a theoretical approach based on molecular docking, molecular dynamics, and density functional theory calculations.

Chagas disease (CD) is a tropical disease caused by the parasite Trypanosoma cruzi, transmitted by the barber insect. Currently, there are approximately 7 million infected people in the world, and it is estimated that 70 million people could contract this disease. The anacardic acid (AA) showed effectiveness in in silico and in vitro tests. The antichagasic potential of five sulfonamide molecules, derived from anacardic acid, was evaluated from a molecular approach based on the density functional theory (DFT), molecular dynamics (MD), and molecular docking (docking) calculations. Methyl 2-methoxy-6- (8- (methylsulfonamide) octyl) benzoate (SA1); 2-methoxy-6- (8- (phenylsulfonamide) octyl) benzoate (SA2); methyl 2-methoxy-6- (8- (2methylphenyl sulfonamide) octyl) benzoate (SA3); methyl 2-methoxy-6- (8-(methylphenylsulfonamide)octyl)benzoate (SA4); methyl2-(8-(2,5-dimethylphenylsulfonamide)octyl)-6-methoxybenzoate (SA5) were the investigated molecules. The DFT calculations were performed using the B3LYP/6-311+G (d, p) level of theory. The global and local reactivity data showed that SA1 shows the highest molecular reactivity, while SA2 is the most stable derivative. In addition, the structures of investigated molecules were confirmed by the linear correlations higher than 0.98 displayed between the experimental and calculated spectroscopic data (IR and NMR). Molecular docking of the molecules showed a greater prominence for the SA1, SA2, and SA4 molecules in the results of distances of ligand-cruzain. In molecular dynamics, SA2 obtained better stability due to greater interactions with important amino acids of cruzain.

Synthesis of aminochalcones and in silico evaluation of their antiparasitic potential against Leishmania.

Leishmaniasis disease is a serious public health problem. This disease reaches about 10 to 12 million people, and 20-30 thousand people die yearly. The disease treatment is realized through pentavalent antimonial and glucantime. However, some studies indicated that these drugs presented high toxicity and cost. Therefore, it is urgent the search for new drugs that may combat this disease and are less toxic. This work analyzed for the first time the interaction potential of (E)-1-(4-aminophenyl)-3-phenylprop-2-en-1-one (C1), (E)-1-(4-aminophenyl)-3-(4-methoxyphenyl)-prop-2-en-1-one (C4), (E)-1-(4-aminophenyl)-3-(4ethoxyphenyl)-prop-2-en-1-one (C9) chalcones through in silico approach. The molecular docking and the molecular electrostatic potential results indicated that the chalcones analyzed presented a strong interaction with the Leishmania major receptor, with affinity energy similar to the ligand co-crystallized. Besides, the interaction potential energy analysis from molecular dynamics simulations indicated the C9 ligand interacted more strongly than the 4-bromo-2,6-dichloro-N-(1,3,5-trimethyl-1H-pyrazolyl) benzenesulfonamide ligand with the Leishmania major receptor, especially for the Phe 88, Tyr 217 and His 219 residues. Therefore, the C9 chalcone might potentially treat Leishmaniasis disease.Communicated by Ramaswamy H. Sarma.

The search for new efficient inhibitors of SARS-COV-2 through the De novo drug design developed by artificial intelligence.

The pandemic caused by Sars-CoV-2 is a viral infection that has generated one of the most significant health problems worldwide. Previous studies report the main protease (Mpro) as a potential target for this virus, as it is considered a crucial enzyme in mediating replication and viral transcription. This work presented the construction of new bioactive compounds for possible inhibition. The De novo molecular design of drugs method in the incremental construction of a ligant model within a receptor model was used, producing new structures with the help of artificial intelligence. The research algorithm and the scoring function responsible for predicting orientation and affinity in the molecular target at the time of coupling showed, as a result of the simulation, the compound with the highest bioaffinity value, Hit 998, with the energy of -17.62 kcal/mol, and synthetic viability close to 50%. While hit 1103 presented better synthetic viability (80%), its affinity energy of -10.28 kcal/mol. Both were compared with the reference linker N3, with a binding affinity of -7.5 kcal/mol. ADMET tests demonstrated that simulated compounds have a low risk of metabolic activation and do not exert effective distribution in the CNS, suggesting a pharmacokinetic mechanism based on local action, even with high topological polarity, which resulted in low oral bioavailability. In conclusion, MMGBSA, H-bonds, RMSD, SASA, and RMSF values were also obtained through molecular dynamics to verify the stability of the receptor-ligant complex within the active protein site to seek new therapeutic propositions in the fight against the pandemic.Communicated by Ramaswamy H. Sarma.

Seasonal variation of the composition of essential oils from Piper cernuum Vell and Piper rivinoides Kunth, ADMET study, DFT calculations, molecular docking and dynamics studies of major components as potent inhibitors of the heterodimer methyltransferase complex NSP16-NSP10 SARS COV-2 protein.

Coronavirus disease (COVID-19) has the virus that causes the SARS-CoV-2 severe acute respiratory syndrome, which has reached a pandemic proportion, with thousands of deaths worldwide already registered. It has no standardized effective clinical treatment, arousing the urgent need for the discovery of bioactive compounds for the treatment of symptoms of COVID-19. In this context, the present study aimed to evaluate the influence of seasonality on the yield and chemical composition of the essential oils of Piper cernuum and Piper rivinoides as well as to evaluate the anti-SARS-CoV-2 potential of the major components of each oil by molecular docking and quantum chemical calculation (Density Functional Theory method), being possible indicate that the winter and autumn periods, the seasons of the year where it is possible to obtain the highest percentage of Piper cernuum and Piper rivinoides oils, respectively. Regarding the anti-SARS-Cov-2 potential, the present work showed that the dihydroagarofuran present in Piper cernuum, presented a strong interaction with amino acid residues from Mpro, presenting a potential similar to Remdesivir, a drug for clinical use. Regarding methyltransferase, dihydroagarofuran (Piper cernuum) and myristicin (Piper rivinoids) showed better affinity, with important interactions at the active site of the inhibitor Sinefugin, suggesting a potential inhibitory effect of the heterodimer methyltransferase complex NSP16-NSP10 SARS Cov-2. Molecular docking and molecular dynamics studies represent an initial step, being indicative for future in vitro studies of dihydroagarofuran and myristicin, as possible pharmacological tools for COVID-19.Communicated by Ramaswamy H. Sarma.

Modifiable behavioral risk factors for NCDs and sleep in Brazilian adolescents / Fatores de risco comportamentais modificáveis para DNT e sono em adolescentes brasileiros

ABSTRACT OBJECTIVE To analyze the association between modifiable behavioral risk factors for non-communicable diseases and sleep parameters in Brazilian adolescents. METHODS This was a cross-sectional study that used data from the RPS Cohort Consortium, São Luís, Brazil for the follow-up of adolescents aged 18-19 years (n = 2,515). The outcomes were excessive daytime sleepiness (Epworth Sleepiness Scale - ESS) and sleep quality (Pittsburgh Sleep Quality Index - PSQI). The exposures of interest were the behavioral risk factors for non-communicable diseases (NCDs): screen time, physical inactivity, alcohol, smoking, illicit drugs, caffeine intake, and consumption of sugar-sweetened beverages. Excess weight was considered a possible mediator of this association between the exposures of interest and the outcomes. The models were analyzed by modeling with structural equations. RESULTS Physical inactivity (standardized coefficient, SC = 0.112; p = 0.001), higher consumption of alcohol (SC = 0.168; p = 0.019) and of sugar-sweetened beverages (SC = 0.128; p < 0.001) were associated with excessive daytime sleepiness in adolescents; better socioeconomic status was also associated with this outcome (SC = 0.128; p < 0.001). Physical inactivity (SC = 0.147; p < 0.001) and higher consumption of sugar-sweetened beverages (SC = 0.089; p = 0.003) were also associated with poor sleep quality. Overweight was neither a mediator nor associated with sleep quality or excessive daytime sleepiness. CONCLUSIONS The main modifiable behavioral risk factors for NCDs are associated with worse sleep parameters already in adolescence, which serves as a warning toward the accumulation of risks for sleep disorders in the future.

RESUMO OBJETIVO Analisar a associação entre fatores de risco comportamentais modificáveis para doenças não transmissíveis e parâmetros do sono em adolescentes brasileiros. MÉTODOS Estudo transversal que utilizou dados do Consórcio de Coortes RPS, São Luís, Brasil para o seguimento de adolescentes de 18-19 anos (n = 2.515). Os desfechos foram a sonolência diurna excessiva (Escala de Sonolência de Epworth - ESE) e a qualidade do sono (Índice de Qualidade do Sono de Pittsburgh - IQSP). As exposições de interesse foram os fatores de risco comportamentais para doenças não transmissíveis (DNT): tempo de tela, inatividade física, álcool, cigarro, drogas ilícitas, consumo de cafeína, consumo de bebidas adoçadas com açúcar. O excesso de peso foi considerado um possível mediador dessa associação entre as exposições de interesse e os desfechos. Os modelos foram analisados por modelagem com equações estruturais. RESULTADOS A inatividade física (Coeficiente padronizado, CP = 0,112; p = 0,001), maior consumo de álcool (CP = 0,168; p = 0,019) e de bebidas adoçadas com açúcar (CP = 0,128; p < 0,001) foram associados a sonolência diurna excessiva nos adolescentes; a melhor situação socioeconômica também foi associada a este desfecho (CP = 0,128; p < 0,001). A inatividade física (CP = 0,147; p < 0,001) e o maior consumo de bebidas adoçadas com açúcar (CP = 0,089; p = 0,003) também se associaram com a qualidade do sono ruim. O excesso de peso não foi mediador e nem associado à qualidade do sono ou à sonolência diurna excessiva. CONCLUSÕES Os principais fatores de risco comportamentais modificáveis para DNT estão associados a piores parâmetros do sono já na adolescência; alertando para um quadro de acúmulos de riscos para distúrbios de sono no futuro.

Study of the interactions of di- and tri-terpenes from Stillingia loranthacea with the enzyme NSP16-NSP10 of SARS-CoV-2 / Estudo das interações de di- e tri-terpenos de Stillingia loranthacea com a enzima NSP16-NSP10 de SARS-CoV-2

Objective: This study aimed to evaluate the interactions of di- and tri-terpenes from Stillingia loranthacea with the enzyme NSP16-NSP10 of SARS-CoV-2, important for viral replication. Methods: The molecular docking technique was used to evaluate this interaction. Results: The analysis showed that the evaluated compounds obtained RMSD values of 0.888 to 1.944 Å and free energy of -6.1 to -9.4 kcal/mol, with the observation of hydrogen bonds, salt bridges, and pi-sulfur, pi-alkyl, and hydrophobic interactions. Conclusion: Thus, the results obtained show the potential of the compounds analyzed against the selected target. Since computer simulations are only an initial step in projects for the development of antiviral drugs, this study provides important data for future research.

Objetivo: avaliar as interações de di- e tri-terpenos de Stillingia loranthacea com a enzima NSP16-NSP10 de SARS-CoV-2, importante para a replicação viral. Métodos: A técnica de docking molecular foi utilizada para avaliar essa interação. Resultados: A análise mostrou que os compostos avaliados obtiveram valores de RMSD de 0,888 a 1,944 Å e energia livre de -6,1 a -9,4 kcal/mol, observando-se ligações de hidrogênio, pontes salinas e pi-enxofre, pi-alquil, e interações hidrofóbicas. Conclusão: Assim, os resultados obtidos mostram o potencial dos compostos analisados frente ao alvo selecionado. Como as simulações computacionais são apenas um passo inicial nos projetos de desenvolvimento de medicamentos antivirais, este estudo fornece dados importantes para pesquisas futuras.

Virtual screening based on molecular docking of lysosomotropic compounds as therapeutic agents for COVID-19 / Triagem virtual baseada no encaixe molecular de compostos lisossomotrópicos como agentes terapêuticos para COVID-19

Objective: Analyze lysosomotropic agents and their action on COVID-19 targets using the molecular docking technique. Methods: Molecular docking analyses of these lysosomotropic agents were performed, namely of fluoxetine, imipramine, chloroquine, verapamil, tamoxifen, amitriptyline, and chlorpromazine against important targets for the pathogenesis of SARS-CoV-2. Results: The results revealed that the inhibitors bind to distinct regions of Mpro COVID-19, with variations in RMSD values from 1.325 to 1.962 Å and binding free energy of -5.2 to -4.3 kcal/mol. Furthermore, the analysis of the second target showed that all inhibitors bonded at the same site as the enzyme, and the interaction resulted in an RMSD variation of 0.735 to 1.562 Å and binding free energy ranging from -6.0 to -8.7 kcal/mol. Conclusion: Therefore, this study allows proposing the use of these lysosomotropic compounds. However, these computer simulations are just an initial step toward conceiving new projects for the development of antiviral molecules.

Objetivo: aAnalisar agentes lisossomotrópicos e sua ação em alvos de COVID-19 usando a técnica de docking molecular. Métodos: Foram realizadas análises de docagem molecular destes agentes lisossomotrópicos, nomeadamente de fluoxetina, imipramina, cloroquina, verapamil, tamoxifeno, amitriptilina e clorpromazina contra alvos importantes para a patogenia do SARS-CoV-2. Resultados: Os resultados revelaram que os inibidores se ligam a regiões distintas do Mpro COVID-19, com variações nos valores de RMSD de 1.325 a 1.962 Å e energia livre de ligação de -5,2 a -4,3 kcal/mol. Além disso, a análise do segundo alvo mostrou que todos os inibidores se ligaram no mesmo sítio da enzima, e a interação resultante em uma variação de RMSD de 0,735 a 1.562 Å e energia livre de ligação variando de -6,0 a -8,7 kcal/mol. Conclusão: Portanto, este estudo permite propor o uso desses compostos lisossomotrópicos. No entanto, essas simulações em computador são apenas um passo inicial para a concepção de novos projetos para o desenvolvimento de moléculas antivirais.

(Bio)Sensing Strategies Based on Ionic Liquid-Functionalized Carbon Nanocomposites for Pharmaceuticals: Towards Greener Electrochemical Tools.

The interaction of carbon-based nanomaterials and ionic liquids (ILs) has been thoroughly exploited for diverse electroanalytical solutions since the first report in 2003. This combination, either through covalent or non-covalent functionalization, takes advantage of the unique characteristics inherent to each material, resulting in synergistic effects that are conferred to the electrochemical (bio)sensing system. From one side, carbon nanomaterials offer miniaturization capacity with enhanced electron transfer rates at a reduced cost, whereas from the other side, ILs contribute as ecological dispersing media for the nanostructures, improving conductivity and biocompatibility. The present review focuses on the use of this interesting type of nanocomposites for the development of (bio)sensors specifically for pharmaceutical detection, with emphasis on the analytical (bio)sensing features. The literature search displayed the conjugation of more than 20 different ILs and several carbon nanomaterials (MWCNT, SWCNT, graphene, carbon nanofibers, fullerene, and carbon quantum dots, among others) that were applied for a large set (about 60) of pharmaceutical compounds. This great variability causes a straightforward comparison between sensors to be a challenging task. Undoubtedly, electrochemical sensors based on the conjugation of carbon nanomaterials with ILs can potentially be established as sustainable analytical tools and viable alternatives to more traditional methods, especially concerning in situ environmental analysis.

Antioxidant activity of eugenol and its acetyl and nitroderivatives: the role of quinone intermediates-a DFT approach of DPPH test.

This work investigated the antioxidant potential of acetylated and nitrated eugenol derivatives through structural analysis and the mechanism of hydrogen atomic transfer (HAT) by density functional theory (DFT). The structures were optimized by the hybrid functional M06-2X with basis set 6-31 + G(d,p), and the HAT mechanism was evaluated with HO, HOO, CH3O, DPPH radicals. In agreement with experimental data from previous studies, two steps of hydrogen transfer were tested. The thermodynamic data showed the need for two hydrogen atomic transfer steps from antioxidants, followed by the formation of p-quinomethanes (27, 28, and 29) to make the reaction spontaneous with DPPH. Furthermore, theoretical kinetic data showed that the preferred antioxidant site depends on the instability of the attacking radical and confirmed the antioxidant profile for eugenol (1, 4-allylbenzene-1,2-diol), and nitro-derivative 7 (5-allyl-3-nitrobenzene-1,2-diol) in the DPPH assay. Finally, this study showed that nitro compound 6 (4-allyl-2-methoxy-6-nitrophenol) also has anti-radical activity with smaller radicals but is not observed in the experiment due to structural characteristics and chemoselectivity of DPPH.

Chloride substitution on 2-hydroxy-3,4,6-trimethoxyphenylchalcones improves in vitro selectivity on Trypanosoma cruzi strain Y.

Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR.

Quantum mechanical, molecular docking, molecular dynamics, ADMET and antiproliferative activity on Trypanosoma cruzi (Y strain) of chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(3-nitrophenyl)prop-2-en-1-one derived from a natural product.

Chagas disease is a leading public health problem. More than 8 million people are affected by the disease, which is endemic in 21 countries in Latin America, generating an average annual cost of 7.2 billion dollars per year. The conventional treatment of Chagas disease is carried out by administering the drug benznidazole (BZN), which has caused numerous adverse reactions. Hence, the search for new, more efficient, and less toxic anti-chagasic agents is essential. Recently, chalcones have been researched to propose new therapies against neglected diseases, mainly Trypanosoma cruzi. The objective of this work was to evaluate for the first time the antiproliferative potential of chalcone derived from the natural product on T. cruzi strain Y. The molecular structure of the chalcone was confirmed by spectrometric data. The toxicity of chalcone in LLC-MK2 cells indicated that a concentration of 514.10 ± 62.40 µM was able to reduce cell viability by 50%. Regarding the effect of chalcone on epimastigote forms, an IC50 value of 46.57 ± 9.81 µM was observed; 45.92 ± 8.42 and 16.32 ± 3.41 µM at times of 24, 48 and 72 hours, respectively. The chalcone was able to eliminate trypomastigote forms at all concentrations tested, except for 31.25 µM, with LC50 values of 117.90 ± 12.60 µM, lower than the reference drug BZN (161.40 ± 31. 80 µM). The mechanism of action may be related to the membrane damage provoked by reduction of the mitochondrial potential. The anti-T. cruzi effect can be assigned through some structural aspects of the chalcone as the nitro group (NO2) is present, which can be enzymatically reduced forming a nitro radical, and the presence of methoxyl groups in the A ring of the chalcone. In silico studies showed that the chalcone had a higher affinity for cruzain when compared to BZN and the co-crystallized inhibitor KB2, as it presented a more thermodynamically stable complex in the order of -6.9 kcal mol-1. The pharmacokinetic prediction showed a significant probability of antiprotozoal activity, a good volume of distribution after being absorbed in the intestine, and a low chance of activity in the central nervous system. Therefore, these results suggest that the chalcone can become a potential cruzain enzyme inhibitor with trypanocidal activity.

Electrochemical and theoretical investigation on the behavior of the Co2+ ion in three eutectic solvents.

Deep eutectic solvents (DESs) have many advantages, making them a promising alternative in replacing ionic liquids and organic solvents. Besides, DESs have received much prominence due to their diverse applications: Electrodeposition of metals, organic synthesis, gas adsorption, and biodiesel production. Therefore, this work analyzed the effect of the temperature increase (298 K-353 K) on the behavior of the Co2+ ions in three eutectic solvents through electrochemical techniques and computational simulations. From the electrochemical analysis realized, the increase in temperature caused a reduction in specific mass and an increase in the diffusion coefficient. Besides, the activation energy values were of 15.3, 29.9, and 55.2 kJ mol-1 for 1ChCl:2 EG, 1ChCl:2U, and 1ChCl:2G, respectively. The computational simulations indicate that the increased temperature effect caused the replacement of HBD molecules by anions chloride around Co2+ ions for the SDW1 and SDW3 systems between the temperatures of 298 K-353 K, except for the SDW2 system that the replaced occurred in the interval of 313 K-353 K. Besides, the increase of temperature occasioned the increase of strength for Co-Cl interaction and weakened the interactions between the Co2+ ions with the oxygen of HBD molecules.

Antiproliferative activity on Trypanosoma cruzi (Y strain) of the triterpene 3ß,6ß,16ß-trihidroxilup-20 (29)-ene isolated from Combretum leprosum.

Chagas disease infects approximately seven million people worldwide. Benznidazole is effective only in the acute phase of the disease, with an average cure rate of 80% between acute and recent cases. Therefore, there is an urgent need to find new bioactive substances that can be effective against parasites without causing so many complications to the host. In this study, the triterpene 3ß-6ß-16ß-trihydroxilup-20 (29)-ene (CLF-1) was isolated from Combretum leprosum, and its molecular structure was determined by NMR and infrared spectroscopy. The CLF-1 was also evaluated in vitro and in silico as potential trypanocidal agent against epimastigote and trypomastigote forms of Trypanosoma cruzi (Y strain). The CLF-1 demonstrated good results highlighted by lower IC50 (76.0 ± 8.72 µM, 75.1 ± 11.0 µM, and 70.3 ± 45.4 µM) for epimastigotes at 24, 48 and 72 h, and LC50 (71.6 ± 11.6 µM) for trypomastigotes forms. The molecular docking study shows that the CLF-1 was able to interact with important TcGAPDH residues, suggesting that this natural compound may preferentially exert its effect by compromising the glycolytic pathway in T. cruzi. The ADMET study together with the MTT results indicated that the CLF-1 is well-absorbed in the intestine and has low toxicity. Thus, this work adds new evidence that CLF-1 can potentially be used as a candidate for the development of new options for the treatment of Chagas disease.Communicated by Ramaswamy H. Sarma.

Reabilitação Respiratória para pacientes submetidos à cirurgia torácica e abdominal / Respiratory rehabilitation for patients submitted to thoracic and abdominal surgery

Objetivo: descrever a experiência relacionada a reabilitação respiratória para pacientes submetidos à cirurgia torácica e abdominal superior durante a execução de um programa de extensão universitária. Método: relato de experiência, com abordagem descritiva, sobre a criação de um programa interdisciplinar de reabilitação respiratória para pacientes submetidos à cirurgia torácica e abdominal superior com parceria entre universidade pública e hospital municipal de Imperatriz, Maranhão. Resultados: as atividades do programa universitário de reabilitação respiratória para pacientes em pós-operatório são desempenhadas em três eixos in locus: Educação em Exercícios Respiratórios, Capacitação sobre assistência de enfermagem no pós-operatório de cirurgias torácicas e abdominais e, Educação em saúde e intervenções de enfermagem na atenção ao paciente no período pós-operatório. Conclusão: a atuação em projeto respiratório interdisciplinar, focado em ações educativas, mostrou-se uma ferramenta inovadora de apoio ao cuidado clínico de pacientes submetidos à cirurgia torácica e abdominal superior. (AU)

Objective: To describe the experience related to respiratory rehabilitation for patients undergoing thoracic and upper abdominal surgery during the execution of a university extension program. Methods: Experience report, with a descriptive approach, on the creation of an interdisciplinary program of respiratory rehabilitation for patients undergoing thoracic and upper abdominal surgery in partnership with a public university and a municipal hospital in Imperatriz, Maranhão. Results: The activities of the university respiratory rehabilitation program for patients in the postoperative period are performed in three axes in locus: Education in Respiratory Exercises, Training in nursing care in the postoperative period of thoracic and abdominal surgeries, and Health education and interventions nursing in patient care in the postoperative period. Conclusion: Acting in an interdisciplinary respiratory project, focused on educational actions, proved to be an innovative tool to support the clinical care of patients undergoing thoracic and upper abdominal surgery. (AU)

Objetivo: Describir la experiencia relacionada con la rehabilitación respiratoria para pacientes sometidos a cirugía torácica y abdominal superior durante la ejecución de un programa de extensión universitaria. Métodos: Informe de experiencia, con un enfoque descriptivo, sobre la creación de un programa interdisciplinario de rehabilitación respiratoria para pacientes sometidos a cirugía torácica y abdominal superior en colaboración con una universidad pública y un hospital municipal en Imperatriz, Maranhão. Resultados: Las actividades del programa universitario de rehabilitación respiratoria para pacientes en el postoperatorio se realizan en tres ejes en el locus: educación en ejercicios respiratorios, capacitación en cuidados de enfermería en el postoperatorio de cirugías torácicas y abdominales, y educación e intervenciones de salud enfermería en atención al paciente en el postoperatorio. Conclusión: Actuar en un proyecto respiratorio interdisciplinario, centrado en acciones educativas, demostró ser una herramienta innovadora para apoyar la atención clínica de pacientes sometidos a cirugía torácica y abdominal superior. (AU)