Structure-Metabolism Relationships of benzimidazole derivatives with anti-Trypanosoma cruzi activity for Chagas disease.

This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42e and 49b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds.

Synthesis and Anti-Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives.

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1-9 displayed good potency (EC50T. cruzi amastigote <1 µM), and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32-64 µM). Despite the good balance between potency and selectivity, the antiparasitic activity of the series appeared to be driven by lipophilicity, making the progression of the series unfeasible due to poor ADME properties and potential promiscuity issues.

Multi-trait selection for nutritional and physiological quality of cacao genotypes in irrigated and non-irrigated environments.

Water is a scarce, strategic resource and the most important input for economic development, especially in agricultural countries such as Brazil. Cocoa production is directly related to water availability, and, as climate changes, selecting drought-tolerant genotypes is vital to keep cacao crops sustainable. Here, we evaluated cacao genotypes under irrigated and water-stressed conditions and selected drought-tolerant ones based on nutritional and physiological traits. Thirty-nine genotypes were monitored for three years for agronomic traits and higher fruit yield. After this evaluation, the 18 most promising genotypes were evaluated in a randomized block design, under a 2 (with and without irrigation)  ×  18 (genotypes) factorial arrangement, with three replicates and five plants per plot. We evaluated seven physiological and 11 nutritional traits, selecting genotypes based on the Genotype-by-Trait Biplot approach. Significant effects (p < 0.05) were observed for the nutritional traits N, P, Mg, S, Zn, Cu, Mn and for the physiological traits CO2 assimilation rate (A), stomatal conductance (gs), transpiration (E), intercellular and atmospheric CO2 concentrations (Ci/Ca), intrinsic water use efficiency (A/gs), instantaneous water use efficiency (A/E), and instantaneous carboxylation efficiency (A/Ci), as determined by analysis of variance. The genotype  ×  irrigation treatment interaction was significant (p < 0.05) for the traits A, gs, and E. Genotypes CP 41, CP 43, and CCN 51 exhibited superior performance for both nutritional and physiological traits (A, gs, and E). In the irrigated environment, CP 41 showed superiority in traits such as P, A/E, A/gs, Mn, S, and Zn. Conversely, under non-irrigated conditions, CP 43 exhibited better performance in nutritional properties, specifically Mn, Mg, and Zn. Notably, in both irrigated and non-irrigated environments, CCN 51 excelled in key physiological traits, including A/Ci, A/E, and A/gs. This robust performance across diverse conditions suggests that these three genotypes possess physiological mechanisms to endure water-stressed conditions. Our research can generate valuable insights into these genotypes informing suitable choices for cocoa cultivation, especially in the context of global climate change.

GIS-FA: an approach to integrating thematic maps, factor-analytic, and envirotyping for cultivar targeting.

KEY MESSAGE: We propose an "enviromics" prediction model for recommending cultivars based on thematic maps aimed at decision-makers. Parsimonious methods that capture genotype-by-environment interaction (GEI) in multi-environment trials (MET) are important in breeding programs. Understanding the causes and factors of GEI allows the utilization of genotype adaptations in the target population of environments through environmental features and factor-analytic (FA) models. Here, we present a novel predictive breeding approach called GIS-FA, which integrates geographic information systems (GIS) techniques, FA models, partial least squares (PLS) regression, and enviromics to predict phenotypic performance in untested environments. The GIS-FA approach enables: (i) the prediction of the phenotypic performance of tested genotypes in untested environments, (ii) the selection of the best-ranking genotypes based on their overall performance and stability using the FA selection tools, and (iii) the creation of thematic maps showing overall or pairwise performance and stability for decision-making. We exemplify the usage of the GIS-FA approach using two datasets of rice [Oryza sativa (L.)] and soybean [Glycine max (L.) Merr.] in MET spread over tropical areas. In summary, our novel predictive method allows the identification of new breeding scenarios by pinpointing groups of environments where genotypes demonstrate superior predicted performance. It also facilitates and optimizes cultivar recommendations by utilizing thematic maps.

ProbBreed: a novel tool for calculating the risk of cultivar recommendation in multienvironment trials.

Neglecting genotype-by-environment interactions in multienvironment trials (MET) increases the risk of flawed cultivar recommendations for growers. Recent advancements in probability theory coupled with cutting-edge software offer a more streamlined decision-making process for selecting suitable candidates across diverse environments. Here, we present the user-friendly ProbBreed package in R, which allows breeders to calculate the probability of a given genotype outperforming competitors under a Bayesian framework. This article outlines the package's basic workflow and highlights its key features, ranging from MET model fitting to estimating the per se and pairwise probabilities of superior performance and stability for selection candidates. Remarkably, only the selection intensity is required to compute these probabilities. By democratizing this complex yet efficient methodology, ProbBreed aims to enhance decision-making and ultimately contribute to more accurate cultivar recommendations in breeding programs.

Structure-activity relationships of novel N-imidazoylpiperazines with potent anti-Trypanosoma cruzi activity.

Background: Chagas disease is caused by the parasite Trypanosoma cruzi, and the lack of effective and safe treatments makes identifying new classes of compounds with anti-T. cruzi activity of paramount importance. Methods: Hit-to-lead exploration of a metabolically stable N-imidazoylpiperazine was performed. Results: Compound 2, a piperazine derivative active against T. cruzi, was selected to perform the hit-to-lead exploration, which involved the design, synthesis and biological evaluation of 39 new derivatives. Conclusion: Compounds 6e and 10a were identified as optimized compounds with low micromolar in vitro activity, low cytotoxicity and suitable preliminary absorption, distribution, metabolism and excretion and physicochemical properties. Both compounds reduced parasitemia in mouse models of Chagas disease, providing a promising opportunity for further exploration of new antichagasic compounds.

Structure-based discovery of thiosemicarbazones as SARS-CoV-2 main protease inhibitors.

Aim: Discovery of novel SARS-CoV-2 main protease (Mpro) inhibitors using a structure-based drug discovery strategy. Materials & methods: Virtual screening employing covalent and noncovalent docking was performed to discover Mpro inhibitors, which were subsequently evaluated in biochemical and cellular assays. Results: 91 virtual hits were selected for biochemical assays, and four were confirmed as reversible inhibitors of SARS CoV-2 Mpro with IC50 values of 0.4-3 µM. They were also shown to inhibit SARS-CoV-1 Mpro and human cathepsin L. Molecular dynamics simulations indicated the stability of the Mpro inhibitor complexes and the interaction of ligands at the subsites. Conclusion: This approach led to the discovery of novel thiosemicarbazones as potent SARS-CoV-2 Mpro inhibitors.

Fisheries monitoring in Brazil: How can the 2030 agenda be met without fisheries statistics? / Monitoramento da pesca no Brasil: como cumprir a agenda 2030 sem estatísticas da pesca?

Every activity that involves exploitation of natural resources, such as fishing, needs to be organized and conducted based on information from monitoring programs to allow continuous evaluation. With the increasing fishing pressure in Brazil, the understanding of the importance of fisheries monitoring programs and how they can inform and assist in conservation decision-making remains limited. Based on the literature on fisheries and participatory conservation, we call attention to the need to generate information on the national fisheries sector in order to improve fisheries in the country. Given the context of the need to generate information on fishing stocks under exploitation, as well as to identify potential alternative fisheries and carry out various sectoral analyses in compliance with the 2030 Agenda for Sustainable Development, we present and discuss in the present paper the lack of a system of continuous fishing monitoring in Brazil and its effects on the fisheries sustainability in the country.

Toda atividade que atua envolvendo a exploração de recursos naturais, como a pesca, precisa ser organizada e conduzida com base nas informações dos programas de monitoramento para permitir uma avaliação contínua. Com o aumento da pressão pesqueira no Brasil, o entendimento da importância dos programas de monitoramento da pesca e como eles podem informar e auxiliar na tomada de decisões de conservação permanece limitado. Com base na literatura sobre pesca e conservação participativa, chamamos a atenção para a necessidade de gerar informações sobre o setor pesqueiro nacional para melhorar a pesca no país. Dado o contexto da necessidade de gerar informações sobre os estoques pesqueiros em exploração, bem como identificar potenciais alternativas de pesca e realizar diversas análises setoriais em conformidade com a Agenda 2030 para o Desenvolvimento Sustentável, é apresentada e discutida no presente trabalho a falta de um sistema de monitoramento contínuo da pesca no Brasil e seus efeitos na sustentabilidade da pesca no país.

Hit-to-lead optimization of a 2-aminobenzimidazole series as new candidates for chagas disease.

Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. Because current treatments present several limitations, including long duration, variable efficacy and serious side effects, there is an urgent need to explore new antitrypanosomal drugs. The present study describes the hit-to-lead optimization of a 2-aminobenzimidazole hit 1 identified through in vitro phenotypic screening of a chemical library against intracellular Trypanosoma cruzi amastigotes, which focused on optimizing potency, selectivity, microsomal stability and lipophilicity. Multiparametric Structure-Activity Relationships were investigated using a set of 277 derivatives. Although the physicochemical and biological properties of the initial hits were improved, a combination of low kinetic solubility and in vitro cytotoxicity against mammalian cells prevented progression of the best compounds to an efficacy study using a mouse model of Chagas disease.

Genetic variability of cocoa from the amazon basin: implications for genetic conservation

The cocoa and chocolate production chain involves US$60 billion annually and three million farmers around the world, in an area exceeding nine million hectares. The use of wild germplasm will enable to generate new disease- and pest-resistant cultivars and ability to adapt to changing environments. Here we evaluated 145 cocoa accessions, originated from nine Amazonian basins, based on eight fruit traits. Univariate anova showed significant differences (p<0.05) for all traits. For seven traits, the variance component within basins was higher (81.5%, on average). Therefore, it is recommended that the collection of wild accessions prioritize a larger number of plants from a few populations of the most divergent basins. The multivariate analyses revealed a greater divergence between the Ji-Paraná-RO and Solimões/Amazonas-PA basins (27.69) and a greater similarity between Alien clones-PER and Solimões/Amazonas-AM (0.66) in relation to their populations. They also revealed that the accessions differentiation occurred according to the river basin system. These results allowed elucidate the genetic structure and distribution of cacao populations. In addition, strengthen the importance of collecting and conserving germplasm to preserve genetic resources.

Evaluation of adaptability and stability for iron, zinc and protein content in cowpea genotypes using GGE biplot approach.

Cowpea is a widely cultivated crop in the world. Biofortification strategies aim to reduce mineral and protein deficiencies, especially among the poorest people. The aim of this study was to estimate adaptability and stability of cowpea genotypes for iron, zinc and protein contents, through GGE biplot analysis. Twenty cowpea genotypes were evaluated in the municipalities of Piauí Monsenhor Hipólito, Pio IX and São Miguel do Tapuio, under rainfed conditions. The experimental design was a randomized block design with four replications. The traits evaluated were grain yield, iron, zinc and protein contents in dry grains. Iron (Fe) and zinc (Zn) were determined by flame atomic absorption spectrophotometer, and protein contents by Kjeldahl methods. Adaptability and stability were evaluated by GGE biplot analyses. The means of the experiments were 1,209.1 kg ha-1, 51.1 mg kg-1, 46.8 mg kg-1 and 24.3% for grain yield, Fe, Zn and protein contents, respectively. The joint analysis of variance showed significant difference (p < 0.05) for the effect of interaction genotypes by environments for Fe, Zn and protein contents. The lines G6 and G8 were the most promising for grain yield, mineral and protein content through adaptability and stability by GGE biplot approach.

From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds.

Chagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6-7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC50 26 µM, Ki 3 µM) and TbrCatL (IC50 50 µM), two cysteine proteases considered promising drug targets for trypanosomiasis. Here, we describe the design and synthesis of derivatives of our lead compound. The new thiosemicarbazone derivatives showed potency in the nanomolar concentration range against the two enzymes, but they were later characterized as aggregators. Nevertheless, the thiosemicarbazone derivatives showed promising antiparasitic activities against T. b. brucei (EC50 13-49.7 µM) and T. cruzi (EC50 0.027-0.59 µM) under in vitro conditions. The most active thiosemicarbazone was 200-fold more potent than the current anti-chagasic drug, benznidazole, and showed a selectivity index of 370 versus myoblast cells. We have identified an excellent candidate for further optimization and in vivo studies.

Chagas Disease Drug Discovery in Latin America-A Mini Review of Antiparasitic Agents Explored Between 2010 and 2021.

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi that endangers almost 70 million people worldwide. The only two drugs that are currently approved for its treatment, benznidazole and nifurtimox, have controversial efficacy in adults and restricting safety issues, leaving thousands of patients without a suitable treatment. The neglect of Chagas disease is further illustrated by the lack of a robust and diverse drug discovery and development portfolio of new chemical entities, and it is of paramount importance to build a strong research and development network for antichagasic drugs. Focusing on drug discovery programs led by scientists based in Latin America, the main endemic region for this disease, we discuss herein what has been published in the last decade in terms of identification of new antiparasitic drugs to treat Chagas disease, shining a spotlight on the origin, chemical diversity, level of characterization of hits, and strategies used for optimization of lead compounds. Finally, we identify strengths and weaknesses in these drug discovery campaigns and highlight the importance of multidisciplinary collaboration and knowledge sharing.

Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors.

Natural products based on imidazole scaffolds have inspired the discovery of a wide variety of bioactive compounds. Herein, a series of imidazoles that act as competitive and potent cruzain inhibitors was investigated using a combination of ligand- and structure-based drug design strategies. Quantitative structure-activity relationships (QSARs) were generated along with the investigation of enzyme-inhibitor molecular interactions. Predictive hologram QSAR (HQSAR, r2pred = 0.80) and AutoQSAR (q2 = 0.90) models were built, and key structural properties that underpin cruzain inhibition were identified. Moreover, comparative molecular field analysis (CoMFA, r2pred = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2pred = 0.73) revealed 3D molecular features that strongly affect the activity of the inhibitors. These findings were examined along with molecular docking studies and were highly compatible with the intermolecular contacts that take place between cruzain and the inhibitors. The results gathered herein revealed the main factors that determine the activity of the imidazoles studied and provide novel knowledge for the design of improved cruzain inhibitors.

2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling.

Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro properties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 µM) and 39 (L. infantum IC50: 0.5 µM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.

Multiparameter Optimization of Trypanocidal Cruzain Inhibitors With In Vivo Activity and Favorable Pharmacokinetics.

Cruzain, the main cysteine protease of Trypanosoma cruzi, plays key roles in all stages of the parasite's life cycle, including nutrition acquisition, differentiation, evasion of the host immune system, and invasion of host cells. Thus, inhibition of this validated target may lead to the development of novel drugs for the treatment of Chagas disease. In this study, a multiparameter optimization (MPO) approach, molecular modeling, and structure-activity relationships (SARs) were employed for the identification of new benzimidazole derivatives as potent competitive inhibitors of cruzain with trypanocidal activity and suitable pharmacokinetics. Extensive pharmacokinetic studies enabled the identification of metabolically stable and permeable compounds with high selectivity indices. CYP3A4 was found to be involved in the main metabolic pathway, and the identification of metabolic soft spots provided insights into molecular optimization. Compound 28, which showed a promising trade-off between pharmacodynamics and pharmacokinetics, caused no acute toxicity and reduced parasite burden both in vitro and in vivo.

Evaluation of anxiety, depression and stress symptoms in men with prostate cancer during the preoperative period / Avaliação dos sintomas de ansiedade, depressão e estresse em homens com câncer de próstata no período pré-operatório

Prostate cancer is the second most common type of cancer among men, being considered a cancer of the elderly because about three quarters of cases worldwide occur in individuals aged 65 and over. Anxiety, depression and stress are three emotional states understood as psychological morbidity factors, and they interfere with the patient's adaptation to the diagnosis. The present study aimed to identify anxiety, depression and stress levels in men with prostate cancer, describing sociodemographic and clinical characteristics and investigating whether the influence of such characteristics on the emotional symptoms of patients is significant. Cross-sectional study with a quantitative approach performed in two public hospitals with patients preoperatively for prostatectomy. Two instruments were used, one covering sociodemographic and clinical aspects of the patients, and the other was the Depression Anxiety and Stress Scale (DASS-21)-Short Form. In the statistical analysis, the Pearson correlation test and the Mann-Whitney U test were used to evaluate the variables of interest, considering the significance level of 0.05. As a preliminary study, 31 patients were interviewed. The results indicated a predominant age of 60 years or older (72.4%), 71% of men had low level of education, and 51.6% did not have partner. The mean scores obtained in the DASS-21 were 2.84 (SD = 3.925) for depression; 3.68 (SD = 3.655) for anxiety; and 6.71 (SD = 6.92) for stress. The results revealed no significant correlation between these constructs and the variables of interest. However, a descriptive analysis of the data showed a minimal correlation of anxiety (r = 0.191) and stress (r = 0.149) with the numerical variable time since diagnosis. In conclusion, the results presented important questions related to prostate cancer diagnosis, involving patients' marital status, religion and cancer staging.

O câncer de próstata é o segundo tipo de neoplasia mais comum entre os homens, sendo considerado um câncer da terceira idade, uma vez que cerca de três quartos dos casos no mundo ocorrem a partir dos 65 anos. Ansiedade, depressão e estresse são três estados emocionais, entendidos como fatores de morbidade psicológica, que interferem na adaptação do paciente ao diagnóstico. O presente estudo teve como objetivo identificar os níveis de ansiedade, depressão e estresse em homens com câncer de próstata; descrever as características sociodemográficas e clínicas e verificar se a influência de tais características é significativa sobre os sintomas emocionais dos pacientes. Estudo transversal, com abordagem quantitativa, realizado em duas instituições hospitalares públicas com os pacientes no pré-operatório para prostatectomia. Foram utilizados dois instrumentos, referente a questões sociodemográficas e clínicas dos pacientes; e a Escala de Depressão, Ansiedade e Estresse: Forma reduzida - DASS-21. Para a análise estatística, foi realizado o teste de correlação de Pearson, e o teste U de Mann-Whitney para avaliar as variáveis de interesse, considerando-se o nível de significância igual a 0,05. Tratando-se de um estudo preliminar, foram entrevistados 31 pacientes, onde os resultados apontaram uma idade predominante de 60 anos ou mais (72,4%), 71% de homens com baixo nível de escolaridade e 51,6% dos entrevistados não possuíam companheiras. As pontuações médias obtidas pelo instrumento do DASS-21 foram: 2,84 (DP = 3,925) para depressão; 3,68 (DP = 3,655) para ansiedade e 6,71 (DP = 6,92) para estresse. Os resultados não revelaram nenhuma correlação significativa entre esses constructos e as variáveis de interesse. No entanto, ao analisar nossos dados de forma descritiva, conseguimos observar mínimas correlações dos sintomas de ansiedade (r = 0,191) e estresse (r = 0,149) com a variável numérica: tempo desde o diagnóstico. Em conclusão, os resultados apresentaram questões importantes relacionadas ao diagnóstico do câncer de próstata, envolvendo o estado civil dos pacientes, a religião e o estadiamento do câncer.

Exogenous brassinosteroids increase lead stress tolerance in seed germination and seedling growth of Brassica juncea L.

Lead (Pb) is a highly toxic heavy metal to plants, animals, and human beings. The use of growth regulators has reversed the effects of heavy metal stress on germination and early plant development. The aim of this study was to evaluate the effect of brassinosteroids on seed germination and seedling growth of Brassica juncea (L.) Czern. & Coss. under Pb stress conditions. Two forms of application of 24-epibrassinolide (EBL) were evaluated, application on seeds in pre-soaking and on germination paper, using EBL concentrations of 0, 10-10, 10-8, and 10-6 M. Germination and seedling growth parameters were evaluated during the germination test. The activity of the enzymes superoxide dismutase, catalase, peroxidase, and ascorbate peroxidase were determined, as well as the lead content in the seeds and seedlings. The EBL applied at the 10-8 M concentration was the most effective in overcoming Pb stress in both forms of application. The antioxidant enzyme defense system was compromised by Pb exposure. However, 10-8 M EBL increased the activity of antioxidant enzymes such as catalase and peroxidase to overcome the toxic effects caused by Pb. In addition, EBL at the concentration of 10-8 M increased Pb content in seedlings without affecting seedling growth.

Hpv impact on oropharyngeal cancer patients treated at the largest cancer center from Brazil.

Oropharyngeal squamous cell carcinoma (OSCC) is a fatal and highly incident disease. Although tobacco and alcohol consumption are the main risk factors associated with OSCC, a recent significant increase in OSCC HPV16 positive cases in high-income countries has been observed. However, it is not clear whether this change is also present in low- and middle-income countries. In this study, we evaluated HPV16 prevalence in 346 OSCC cases diagnosed in the largest Brazilian oncology public hospital by using the combination of two techniques, HPV16 E6 detection by qPCR and p16 immunohistochemistry. In total, 11.9% of cases were HPV16 E6 positive, 9.2% were p16 positive and 6.1% were positive in both analyses. There was a predominance of keratinizing-SCC, with only four HPV-positive cases showing basaloid-like or non-keratinizing-SCC. HPV infection had no impact on disease-free or overall survival, while alcohol use was an independent prognostic factor for overall survival. Most cases reported a high frequency of tobacco (94.6%) and alcohol consumption (88.2%), were of low education level, and typically presented at advanced clinical stages, indicating that the profile of Brazilian OSCC patients has not changed.

Hit-to-lead optimization of a benzene sulfonamide series for potential antileishmanial agents.

A series of benzene sulphonamides with good potency and selectivity against Leishmania spp. intracellular amastigotes was identified by high-throughput screening. Approximately 200 compounds were synthesized as part of a hit-to-lead optimization program. The potency of the series appears to be strongly dependent on lipophilicity, making the identification of suitable orally available candidates challenging due to poor pharmacokinetics. Despite not identifying a clinical candidate, a likely solvent exposed area was found, best exemplified in compound 29. Ongoing detailed mode-of-action studies may provide an opportunity to use target-based medicinal chemistry to overcome the issues with the current series.