Effect of a thiohydantoin salt derived from l-Arginine on Leishmania amazonensis and infected cells: Insights from biological effects to molecular docking interactions.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.

Mechanical methods for materials concentration of lithium iron phosphate (LFP) cells and product potential evaluation for recycling.

The production and sales of lithium-ion batteries (LIB) are rapidly expanding nowadays, causing a significant impact on the consumption of critical raw materials, such as lithium. Thus, developing and improving methods for the separation and recovery of materials from LIBs is necessary to ensure the supply of critical raw materials, as well as to meet the recycling targets set by some countries. This study evaluated and compared two mechanical routes to concentrate materials of LiFePO4 (LPF) cells. In addition, the economic, environmental, and scarcity risk potential of the products obtained through the best mechanical route were evaluated. The first route involved 6 grinding cycles in a knife mill, followed by particle size separation into 3 fractions. The second route involved a single grinding cycle (knife and hammer mill were tested), followed by particle size separation into 6 fractions. The second route showed more promise, with obtaining fractions rich in (1) iron, (2) aluminum and copper, and (3) cathode materials. Additionally, less operating time and energy consumption were necessary. The hammer mill offered a better separation for the iron and the cathodic materials (LiFePO4), while the knife mill proved to be more effective in concentrating the aluminum and copper. The product potential evaluation of the best route revealed that the priority fractions for recycling in economic and environmental assessment in LFP2 are 2 < n < 9.5 mm (due Cu and Al) and n < 0.5 mm (due Li). Considering the scarcity risk, priority should be assigned to the recycling of the fraction n < 0.5 due to lithium.

Py-CoMFA, docking, and molecular dynamics simulations of Leishmania (L.) amazonensis arginase inhibitors.

Leishmaniasis is a disease caused by a protozoan of the genus Leishmania, affecting millions of people, mainly in tropical countries, due to poor social conditions and low economic development. First-line chemotherapeutic agents involve highly toxic pentavalent antimonials, while treatment failure is mainly due to the emergence of drug-resistant strains. Leishmania arginase (ARG) enzyme is vital in pathogenicity and contributes to a higher infection rate, thus representing a potential drug target. This study helps in designing ARG inhibitors for the treatment of leishmaniasis. Py-CoMFA (3D-QSAR) models were constructed using 34 inhibitors from different chemical classes against ARG from L. (L.) amazonensis (LaARG). The 3D-QSAR predictions showed an excellent correlation between experimental and calculated pIC50 values. The molecular docking study identified the favorable hydrophobicity contribution of phenyl and cyclohexyl groups as substituents in the enzyme allosteric site. Molecular dynamics simulations of selected protein-ligand complexes were conducted to understand derivatives' interaction modes and affinity in both active and allosteric sites. Two cinnamide compounds, 7g and 7k, were identified, with similar structures to the reference 4h allosteric site inhibitor. These compounds can guide the development of more effective arginase inhibitors as potential antileishmanial drugs.

Statine-based peptidomimetic compounds as inhibitors for SARS-CoV-2 main protease (SARS-CoV­2 Mpro).

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.

Molecular modelling studies and in vitro enzymatic assays identified A 4-(nitrobenzyl)guanidine derivative as inhibitor of SARS-CoV-2 Mpro.

Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC50 value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively.

Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.

Tuberculosis (TB) remains a primary global health concern, necessitating the discovery and development of new anti-TB drugs, mainly to combat drug-resistant strains. In this context, thiourea derivatives have emerged as promising candidates in TB drug discovery due to their diverse chemical structures and pharmacological properties. This review aimed to explore this potential, identifying and exploring molecular targets for thiourea derivatives in Mycobacterium tuberculosis (Mtb) and the potential application of virtual screening techniques in drug discovery. We have compiled a comprehensive list of possible molecular targets of thiourea derivatives in Mtb. The enzymes are primarily involved in the biosynthesis of various cell wall components, including mycolic acids, peptidoglycans, and arabinans, or targets in the branched-chain amino acid biosynthesis (BCAA) pathway and detoxification mechanisms. We discuss the potential of these targets as critical constituents for the design of novel anti-TB drugs. Besides, we highlight the opportunities that virtual screening methodologies present in identifying potential thiourea derivatives that can interact with these molecular targets. The presented findings contribute to the ongoing efforts in TB drug discovery and lay the foundation for further research in designing and developing more effective treatments against this devastating disease.

Antiprotozoal Activity of Benzoylthiourea Derivatives against Trypanosoma cruzi: Insights into Mechanism of Action.

For decades, only two nitroheterocyclic drugs have been used as therapeutic agents for Chagas disease. However, these drugs present limited effectiveness during the chronic phase, possess unfavorable pharmacokinetic properties, and induce severe adverse effects, resulting in low treatment adherence. A previous study reported that N-(cyclohexylcarbamothioyl) benzamide (BTU-1), N-(tert-butylcarbamothioyl) benzamide (BTU-2), and (4-bromo-N-(3-nitrophenyl) carbamothioyl benzamide (BTU-3) present selective antiprotozoal activity against all developmental forms of Trypanosoma cruzi Y strain. In this study, we investigated the mechanism of action of these compounds through microscopy and biochemical analyses. Transmission electron microscopy analysis showed nuclear disorganization, changes in the plasma membrane with the appearance of blebs and extracellular arrangements, intense vacuolization, mitochondrial swelling, and formation of myelin-like structures. Biochemical results showed changes in the mitochondrial membrane potential, reactive oxygen species content, lipid peroxidation, and plasma membrane fluidity. In addition, the formation of autophagic vacuoles was observed. These findings indicate that BTU-1, BTU-2, and BTU-3 induced profound morphological, ultrastructural, and biochemical alterations in epimastigote forms, triggering an autophagic-dependent cell death pathway.

Proteasome as a Drug Target in Trypanosomatid Diseases.

Some diseases caused by trypanosomatid parasites, like Leishmaniasis, Chagas Disease, and Human African Trypanosomiasis (HTA), are challenging to manage, mainly concerning pharmacological therapy because they are associated with vulnerable populations. Unfortunately, there is a lack of significant investments in the search for new drugs. Therefore, one of the strategies to aid the discovery of new drugs is to identify and inhibit molecular targets essential to the parasite's survival, such as the proteasome, which degrades most proteins in the parasite cells. Our study has presented several proteasome inhibitors with various pharmacophoric cores, and two of them, 5, and 13, have stood out in the clinical phase of treatment for leishmaniasis.

c-Si PV module recycling: Analysis of the use of a mechanical pre-treatment to reduce the environmental impact of thermal treatment and enhance materials recovery.

The current increase in the use of photovoltaic (PV) energy demands the search for solutions to recycle end-of-life modules. This study evaluated the use of a mechanical pre-treatment in the thermal recycling of c-Si crystalline PV modules, which were submitted to recycling routes to separate and concentrate the materials of interest. The first route was constituted by only thermal treatment, and the second route was constituted by a mechanical pre-treatment to remove the polymers from the backsheet, and subsequent thermal treatment. The exclusively thermal route was performed at 500°C, varying dwell times between 30 and 120 minutes in the furnace. In this route, the best results were obtained in 90 minutes, with a maximum degradation of 68% of the polymeric mass. In route 2, a micro-grinder rotary tool was used to remove the polymers from the backsheet and, subsequently, thermal treatment performed at 500°C, with dwell times in the furnace ranging between 5 and 30 minutes. The mechanical pre-treatment removed about 10.32 ± 0.92% of the mass of the laminate PV module. By this route, only 20 minutes of thermal treatment were needed for the total decomposition of the polymers, that is, a reduction of 78% in the oven time. With route 2, it was possible to obtain a concentrate with 30 times more silver than the PV laminate and 40 times more than a high-concentration ore. Furthermore, with route 2 it was possible to reduce the environmental impact of heat treatment and energy consumption.

In-vitro biological evaluation of 3,3',5,5'-tetramethoxy-biphenyl-4,4'-diol and molecular docking studies on trypanothione reductase and Gp63 from Leishmania amazonensis demonstrated anti-leishmania potential.

Available treatments for leishmaniasis have been widely used since the 1940s but come at a high cost, variable efficacy, high toxicity, and adverse side-effects. 3,3',5,5'-Tetramethoxy-biphenyl-4,4'-diol (TMBP) was synthesized through laccase-catalysis of 2,6-dimethoxyphenol and displayed antioxidant and anticancer activity, and is considered a potential drug candidate. Thus, this study aimed to evaluate the anti-leishmanial effect of TMBP against promastigote and amastigote forms of Leishmania (L.) amazonensis and investigated the mechanisms involved in parasite death. TMBP treatment inhibited the proliferation (IC50 0.62-0.86 µM) and induced the death of promastigote forms by generating reactive oxygen species and mitochondrial dysfunction. In intracellular amastigotes, TMBP reduced the percentage of infected macrophages, being 62.7 times more selective to the parasite (CC50 53.93 µM). TMBP did not hemolyze sheep erythrocytes; indicative of low cytotoxicity. Additionally, molecular docking analysis on two enzyme targets of L. amazonensis: trypanothione reductase (TR) and leishmanolysin (Gp63), suggested that the hydroxyl group could be a pharmacophoric group due to its binding affinity by hydrogen bonds with residues at the active site of both enzymes. TMBP was more selective to the Gp63 target than TR. This is the first report that TMBP is a promising compound to act as an anti-leishmanial agent.

Computational Strategies Targeting Inhibition of Helicobacter pylori and Cryptococcus neoformans Ureases.

Helicobacter pylori and Cryptococcus ssp. are pathogenic ureolytic microorganisms that cause several disorders in the host organism and, in severe cases, lead to death. Both infections have the urease enzyme as a key virulence factor since they use its ability to produce ammonia to soften the inhospitable pH to which they are subjected. In this review, we describe two ureases as possible molecular targets for drug discovery and provide insights for developing potent inhibitors against ureases from these pathogenic microorganisms through computer-aided drug discovery approaches, such as structure-based drug design (SBDD) and structure-activity relationship (SAR). The SAR studies have indicated several essential subunits and groups to be present in urease inhibitors that are critical for inhibitory activity against H. pylori or Cryptococcus spp. Since the threedimensional structure of C. neoformans urease has yet to be determined experimentally, the plant urease of Canavalia ensiformis was used in this study due to its structural similarity. Therefore, in the SBDD context, FTMap and FTSite analyses were performed to reveal characteristics of the urease active sites in two protein data bank files (4H9M, Canavalia ensiformis, and 6ZJA, H. pylori). Finally, a docking-based analysis was performed to explore the best inhibitors described in the literature to understand the role of the ligand interactions with the key residues in complex ligand-urease stabilization, which can be applied in the design of novel bioactive compounds.

Synergistic antifungal interaction of N-(butylcarbamothioyl) benzamide and amphotericin B against Cryptococcus neoformans.

Introduction: Cryptococcus neoformans is one of the leading causes of invasive fungal infections worldwide. Cryptococcal meningoencephalitis is the main challenge of antifungal therapy due to high morbidity and mortality rates, especially in low- and middle-income countries. This can be partly attributed to the lack of specific diagnosis difficulty accessing treatment, antifungal resistance and antifungal toxicity. Methods: In the present study, the effect of the synthetic thiourea derivative N-(butylcarbamothioyl) benzamide (BTU-01), alone and combined with amphotericin B (AmB), was evaluated in planktonic and sessile (biofilm) cells of C. neoformans. Results: BTU-01 alone exhibited a fungistatic activity with minimal inhibitory concentrations (MICs) ranging from 31.25 to 62.5 µg/mL for planktonic cells; and sessile MICs ranging from 125.0 to 1000.0 µg/mL. BTU-01 caused a concentration-dependent inhibitory activity on cryptococcal urease and did not interfere with plasma membrane fluidity. Molecular docking was performed on Canavalia ensiformis urease, and BTU-01 showed relevant interactions with the enzyme. The combination of BTU-01 and AmB exhibited synergistic fungicidal activity against planktonic and sessile cells of C. neoformans. Microscopic analysis of C. neoformans treated with BTU-01, alone or combined with AmB, revealed a reduction in cell and capsule sizes, changes in the morphology of planktonic cells; a significant decrease in the number of cells within the biofilm; and absence of exopolymeric matrix surrounding the sessile cells. Neither hemolytic activity nor cytotoxicity to mammalian cells was detected for BTU-01, alone or combined with AmB, at concentrations that exhibited antifungal activity. BTU-01 also displayed drug-likeness properties. Conclusion: These results indicate the potential of BTU-01, for the development of new strategies for controlling C. neoformans infections.

CYP1B1: A Promising Target in Cancer Drug Discovery.

CYP1B1 plays an essential role in cancer's pathogenesis since it activates procarcinogens. Significantly, this enzyme catalyzes the hydroxylation of 17ß-estradiol, leading to carcinogenic metabolites involved in carcinogenesis and cancer progression. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target for chemotherapy. In addition, CYP1B1 is overexpressed in hormone-dependent cancer cells and could be related to resistance to anticancer drugs. However, the activity of CYP1B1 in the tumor microenvironment can metabolize and activate prodrugs in cancer cells, providing more selectivity and being useful for chemoprevention or chemotherapy strategies. Furthermore, due to its importance in anticancer drug design, recent studies have reported using computational methods to understand the intermolecular interactions between possible ligands and CYP1B1. Therefore, in this perspective, we highlight recent findings in developing CYP1B1 inhibitors (flavonoids, trans-stilbenes, estradiol derivatives, and carbazoles) and CYP1B1-activated prodrugs (a chalcone DMU-135 and an oxime DMAKO-20). Finally, we have analyzed their possible molecular interactions with this enzymatic target by molecular docking, which can help to design new active substances.

In silico approaches and in vitro assays identify a coumarin derivative as antiviral potential against SARS-CoV-2.

COVID-19, a disease caused by SARS-CoV-2, was declared a pandemic in 2020 and created a global crisis in health systems, with more than 545 million confirmed cases and 6.33 million deaths. In this sense, this work aims to identify possible inhibitors of the SARS-CoV-2 RdRp enzyme using in silico approaches. RdRp is a crucial enzyme in the replication and assembly cycle of new viral particles and a critical pharmacological target in the treatment of COVID-19. We performed a virtual screening based on molecular docking from our in-house chemical library, which contains a diversity of 313 structures from different chemical classes. Nine compounds were selected since they showed important interactions with the active site from RdRp. Next, the ADME-Tox in silico predictions served as a filter and selected the three most promising compounds: a coumarin LMed-052, a hydantoin LMed-087, and a guanidine LMed-250. Molecular dynamics simulations revealed details such as changes in the positions of ligands and catalytic residues during the simulations compared to the complex from molecular docking studies. Binding free energy analysis was performed using the MMGBSA method, demonstrating that LMed-052 and LMed-087 have better affinities for the RdRp by energetic contributions to the stability of the complexes when compared to LMed-250. Furthermore, LMed-052 showed significant in vitro inhibition against MHV-3, decreasing 99% of viral titers. Finally, these findings are useful to guide structural modifications aiming to improve the potential of these compounds to act as inhibitors of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

In silico approach identified benzoylguanidines as SARS-CoV-2 main protease (Mpro) potential inhibitors.

The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), became the highest public health crisis nowadays. Although the use of approved vaccines for emergency immunization and the reuse of FDA-approved drugs remains at the forefront, the search for new, more selective, and potent drug candidates from synthetic compounds is also a viable alternative to combat this viral disease. In this context, the present study employed a computational virtual screening approach based on molecular docking and molecular dynamics (MD) simulation to identify possible inhibitors for SARS-CoV-2 Mpro (main protease), an important molecular target required for the maturation of the various polyproteins involved in viral replication. The virtual screening approach selected four potential inhibitors against SARS-CoV-2 Mpro. In addition, MD simulation studies revealed changes in the positions of the ligands during the simulations compared to the complex obtained in the molecular docking studies, showing the benzoylguanidines LMed-110 and LMed-136 have a higher affinity for the active site compared to the other structures that tended to leave the active site. Besides, there was a better understanding of the formation and stability of the existing H-bonds in the formed complexes and the energetic contributions to the stability of the target-ligand molecular complexes. Finally, the in silico prediction of the ADME profile suggested that LMed-136 has drug-like characteristics and good pharmacokinetic properties. Therefore, from the present study, it can be suggested that these structures can inhibit SARS-CoV-2 Mpro. Nevertheless, further studies are needed in vitro assays to investigate the antiviral properties of these structures against SARS-CoV-2.

Disponibilidade, acesso percebido e insegurança alimentar em domicílios de escolares de dois municípios de Minas Gerais na pandemia de COVID-19 / Availability, perceived access, and food insecurity in households of schoolchildren in two cities of Minas Gerais in the COVID-19 pandemic

Introdução: O contexto pandêmico tem implicações diretas na situação de segurança alimentar e nutricional atual e futura, assim é urgente avaliar a situação da insegurança alimentar em suas diferentes dimensões. Há poucos estudos que avaliam conjuntamente segurança alimentar, disponibilidade e acesso aos alimentos. Objetivo: Descrever a disponibilidade alimentar domiciliar e o acesso percebido aos alimentos segundo a situação de insegurança alimentar em domicílios de escolares na pandemia de COVID-19. Métodos: Trata-se de um estudo transversal com amostra representativa de domicílios de escolares da educação infantil e ensino fundamental de escolas públicas de Mariana e Ouro Preto, Minas Gerais. Os dados foram coletados na fase inicial da pandemia, "junho e julho de 2020", por meio de entrevistas telefônicas com os responsáveis por comprar e/ou preparar os alimentos nos domicílios. Investigou-se condições socioeconômicas, acesso percebido aos alimentos, disponibilidade alimentar domiciliar e insegurança alimentar, esta avaliada por meio da Escala Brasileira de Insegurança Alimentar. Resultados: Dos 612 domicílios investigados, 82,0% estavam em situação de insegurança alimentar, sendo 11,3% em insegurança moderada e 5,1% em insegurança grave. Foi observada relação entre disponibilidade de frutas, hortaliças, leite, carnes e ovos com a insegurança alimentar, bem como com a percepção de dificuldade no acesso a frutas e hortaliças. Discussão: A situação de insegurança alimentar enfrentada pelos domicílios relaciona-se com menor disponibilidade de alimentos importantes para o desenvolvimento dos escolares, ademais as famílias depararam com inacessibilidade para adquirir frutas e hortaliças. (AU)

Introduction: The pandemic context impacts the current and future situation of food and nutritional security, so it is urgent to assess the situation of food insecurity in its different dimensions. There are few studies that jointly assess food security, availability, and access to food. Objective: To describe household food availability and perceived access to food according to the situation of food insecurity in households of schoolchildren during the COVID-19 pandemic. Methods: This is a cross-sectional study with a representative sample of households of schoolchildren in early childhood education and elementary school from public schools in Mariana and Ouro Preto, Minas Gerais. Data were collected in the initial phase of the pandemic, "June and July 2020", through telephone interviews with those responsible for buying and/or preparing the food in the households. Socioeconomic conditions, perceived access to food, and household food availability were investigated, and food insecurity was measured using the Brazilian Household Food Insecurity Measurement Scale. Results: Of the 612 households surveyed, 82.0% of the households presented food insecurity, of which 11.3% moderate food insecurity and 5.1% severe food insecurity. A relationship was observed between the low availability of fruits, vegetables, milk, meat, and eggs with food insecurity and the perception of difficulty in accessing fruits and vegetables. Discussion: The situation of food insecurity faced by households is related to low availability of essential foods for the development of schoolchildren, and families also encounter inaccessibility to acquire fruits and vegetables. (AU)

Promising Molecular Targets Related to Polyamine Biosynthesis in Drug Discovery against Leishmaniasis.

Leishmaniasis is a neglected tropical disease widely distributed worldwide, caused by parasitic protozoa of the genus Leishmania. Despite representing a significant public health problem, the therapeutic options are old, with several reported adverse effects, have high costs, with administration mainly by parenteral route, which makes treatment difficult, increasing dropout and, consequently, the emergence of resistant strains. Thus, the research and development of new antileishmanial therapies become necessary. In this field, inhibiting essential targets that affect the parasite's growth, survival, and infectivity represents an attractive therapeutic strategy. With this in mind, this review addresses the main structural, functional characteristics and recent reports of the discovery of promising inhibitors of the enzymes Arginase (ARG) and trypanothione synthase (TryS), which are involved in the biosynthesis of polyamines and trypanothione and Trypanothione Reductase (TR), responsible for the reduction of trypanothione thiol.

Thiohydantoins and hydantoins derived from amino acids as potent urease inhibitors: Inhibitory activity and ligand-target interactions.

We report the investigation of hydantoins and thiohydantoins derived from L and d-amino acids as inhibitors against the Canavalia ensiformis urease (CEU). The biochemical in vitro assay against CEU revealed a promising inhibitory potential for most thiohydantoins with six of them showing %I higher than the reference inhibitor thiourea (56.5%). In addition, thiohydantoin derived from l-valine, 1b, as well as the hydantoin 2d, derived from l-methionine, were identified as the most potent inhibitors with %I = 90.5 and 85.9 respectively. Enzyme kinetic studies demonstrated a mixed and uncompetitive inhibition profile for these compounds with Ki values of 0.42 mM for 1b and 0.99 mM for 2d. These kinetic parameters, obtained from traditional colorimetric assay, were strictly related to the KD values measured spectroscopically by the Saturation Transfer Difference (STD) technique for the urease complex. STD was also used to evince the moieties of the ligands responsible for the binding with the enzyme. Molecular docking studies showed that the thiohydantoin and hydantoin rings can act as a pharmacophoric group due to their binding affinity by hydrogen bonding interactions with critical amino acid residues in the enzyme active and/or allosteric site. These findings agreed with the experimental alpha values, demonstrating that 1b has affinity by free enzyme, and 2d derivative, an uncompetitive inhibitor, has great binding affinity at the allosteric site. The results for the thiohydantoin 1a, derived from d-valine, demonstrated a drastic stereochemical influence on inhibition, kinetics, and binding parameters in comparison to its enantiomer 1b.

Cardiovascular Risk Factors in Haul Truck Operators of the Mining Sector Working a Rotational Schedule

Abstract Background: Due to the growing concern about work-related social and health aspects, occupational health and safety has become relevant. Objective: This work aims to develop a model to assist cardiovascular risk management in a team of haul truck operators, who work in rotating shifts at a mining company in Brazil. Methods: This longitudinal study evaluated risk factors for cardiovascular diseases of 191 mineworkers at three times points - 2010, 2012, and 2015. In addition, the risk of developing cardiovascular diseases was calculated, and the risk factors were analyzed using the chi-square test, the U Mann-Whitney test, and binary logistic regression. The significance level was set at 5%. Results: In the study period, body weight, body mass index (BMI), waist-to-height ratio (WHR), systolic (SBP), and diastolic blood pressure (DBP), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides levels of the study group increased. In 2015, there was a high prevalence of alcohol intake, overweight or obesity, central obesity, inadequate WHR, high blood pressure, total cholesterol above 190 mg/dL, and triglycerides above 150 mg/dL. An association was identified between increased cardiovascular risk and age, SBP, HDL-C, low-density lipoprotein cholesterol (LDL-C), and elevated glucose levels. Conclusion: Intense interventions for reduction and prevention of elevated alcohol intake, blood pressure levels, WHR, metabolic syndrome, blood glucose, and LDL-C levels, and low HDL-C levels are needed. In addition, a close monitoring of mine workers over 38 years of age who smoke, consume alcoholic beverages, and have altered blood glucose levels is important.

Brazilian initial experience with lung transplantation due to irreversible lung fibrosis post-COVID-19 in a national reference center: a cohort study

ABSTRACT BACKGROUND: Lung transplantation (LTx) has been discussed as an option for treating irreversible lung fibrosis post-coronavirus disease 2019 (COVID-19), in selected cases. OBJECTIVES: To report on the initial experience and management of end-stage lung disease due to COVID-19 at a national center reference in Brazil. DESIGN AND SETTING: Cohort study conducted at a national reference center for lung transplantation. METHODS: Medical charts were reviewed regarding patients' demographics and pre-COVID-19 characteristics, post-LTx due to COVID-19. RESULTS: Between March 2020 and September 2021, there were 33 cases of LTx. During this period, we evaluated 11 cases of severe COVID-19-related acute respiratory distress syndrome (ARDS) that were potentially candidates for LTx. Among these, LTx was only indicated for three patients (9.1%). All of these patients were on venovenous extracorporeal membrane oxygenation (ECMO), and the procedure that they underwent was central venoarterial ECMO. All three patients were still alive after the first 30 postoperative days. However, patient #1 and patient #2 subsequently died due to fungal sepsis on the 47th and 52nd postoperative days, respectively. Patient #3 was discharged on the 30th postoperative day. CONCLUSIONS: LTx is feasible among these complex patients. Survival over the first 30 days was 100%, and this favors surgical feasibility. Nonetheless, these were critically ill patients.