Bruno Antonio Marinho Sanchez

Malaria is a severe parasitic disease, with Plasmodium falciparum as one of the main etiological agents. The growing resistance to antimalarial drugs underscores the urgent need for the development of new therapeutic agents. This study describes the semisynthesis of eight new 1,4‐disubstituted 1,2,3‐triazole derivatives ( 3–10 ) from N , N ‐dimethyltryptamine ( 1 ), isolated from Mimosa tenuiflora . The derivatives were obtained through copper(I)‐catalyzed alkyne–azide cycloaddition (CuAAC) reactions and characterized by NMR and mass spectrometry. Compound 1 showed low in vitro activity against the W2 strain of P. falciparum (IC ₅₀ = 288.4 ± 28.53 µM), whereas compound 4 demonstrated promising activity (IC ₅₀ = 4.8 ± 0.32 µM), with higher selectivity toward the TOV‐21G cell line. In in silico studies, all derivatives showed more favorable binding energy values compared to compound 1 , particularly compound 7 (−9.8 kcal/mol) relative to the crystallographic ligand (−6.9 kcal/mol). These results highlight the importance of structural modifications in the development of new antimalarial agents.

A Leishmaniose Tegumentar Americana (LTA) permanece endêmica no estado de Mato Grosso, Brasil, com alta incidência persistente no município de Sinop. Apesar da disponibilidade de ferramentas diagnósticas e terapêuticas, a LTA continua a representar um importante desafio de saúde pública na região. Foi realizado um estudo epidemiológico descritivo utilizando casos confirmados de LTA notificados em Sinop entre 2010 e 2022. As variáveis analisadas incluíram sexo, idade, etnia, escolaridade, área de residência, critérios diagnósticos, formas clínicas, autoctonia, distribuição temporal e desfechos clínicos. Os dados foram obtidos do Sistema de Informação de Agravos de Notificação (SINAN). No total, 1.354 casos de LTA foram confirmados durante o período do estudo. A doença afetou predominantemente indivíduos do sexo masculino (≈85%), de etnia parda (≈45%), com baixa a média escolaridade, e pertencentes à faixa etária produtiva de 20–39 anos (≈45%). Tanto residentes da zona urbana quanto da zona rural foram acometidos. A forma cutânea representou mais de 95% dos diagnósticos. A maioria dos casos foi confirmada por critérios laboratoriais (90,9%), enquanto o método clínico-epidemiológico respondeu por menos de 10%. Em relação à evolução, a cura foi registrada em 66,3% dos pacientes, mas uma proporção considerável dos desfechos permaneceu ignorada (31,2%). A análise temporal revelou transmissão anual persistente, com picos sazonais nos meses secos (julho–agosto) e predomínio de casos autóctones (67,1%). A LTA em Sinop apresenta um perfil epidemiológico clássico, afetando predominantemente homens jovens, adultos, pardos e com baixa escolaridade, além de demonstrar transmissão endêmica persistente. O predomínio do diagnóstico laboratorial reflete avanços na capacidade de vigilância, embora a elevada proporção de desfechos ignorados evidencie limitações no acompanhamento dos casos. A vigilância contínua, bem como medidas de prevenção e controle, são essenciais para reduzir a carga da doença e interromper a transmissão local.

Dipteryx lacunifera is an example of the Brazilian cerrado flora which recently showed promising biological actions, such as antioxidant and antibacterial activities and a potential antimalarial effect. This study evaluated three flavonoids isolated from the fruits kernels of D. lacunifera, 7,3´, 4´-trihydroxyflavone (1), 7,3´,4´-trihydroxyflavanone (2), and (-)-eriodictyol (3). Virtual molecular modeling platforms (in silico), chemotherapy assays with P. falciparum W2 strain, and cytotoxicity assays (in vitro) were used to verify the antimalarial and cytotoxic potential of these molecules. Compound 2 showed the best results of inhibitory concentration against the P. falciparum W2 strain (IC50 = 7.35 μM), with low cytotoxicity against the human fibroblast lineage (WI- 26-VA4) (LC50 > 100 μM) and high selectivity index (IS = 13.61). In silico analysis of the mechanism of action of 2 was performed by selecting the 5 crystallographic complexes with the best binding energy, namely: 1O5X, 2OK8, 2VFA, 4C81, and 4N0Z, suggesting more than one mode of action. The compounds met the ADMET criteria, indicating good bioavailability results. These results may lead this molecule to be submitted to further studies.

Based on the current need for new drugs against malaria, our study evaluated eight beta amino ketones in silico and in vitro for potential antimalarial activity. Using the Brazilian Malaria Molecular Targets (BraMMT) and OCTOPUS® software programs, the pattern of interactions of beta-amino ketones was described against different proteins of P. falciparum and screened to evaluate their physicochemical properties. The in vitro antiplasmodial activities of the compounds were evaluated using a SYBR Green-based assay. In parallel, in vitro cytotoxic data were obtained using the MTT assay. Among the eight compounds, compound 1 was the most active and selective against P. falciparum (IC₅₀ = 0.98 µM; SI > 60). Six targets were identified in BraMMT that interact with compounds exhibiting a stronger binding energy than the crystallographic ligand: P. falciparum triophosphate phosphoglycolate complex (1LYX), P. falciparum reductase (2OK8), PfPK7 (2PML), P. falciparum glutaredoxin (4N0Z), PfATP6, and PfHT. The physicochemical properties of compound 1 were compatible with the set of criteria established by the Lipinski rule and demonstrated its potential as a drug prototype for antiplasmodial activity.

Background: The resistance against antimalarial drugs represents a global challenge in the fight and control of malaria. The Brazilian biodiversity can be an important tool for research and development of new medicinal products. In this context, toxinology is a multidisciplinary approach on the development of new drugs, including the isolation, purification, and evaluation of the pharmacological activities of natural toxins. The present study aimed to evaluate the cytotoxicity, as well as the antimalarial activity in silico and in vitro of four compounds isolated from Rhinella marina venom as potential oral drug prototypes. Methods: Four compounds were challenged against 35 target proteins from P falciparum and screened to evaluate their physicochemical properties using docking assay in Brazilian Malaria Molecular Targets (BraMMT) software and in silico assay in OCTOPUS (R) software. The in vitro antimalarial activity of the compounds against the 3D7 Plasmodium falciparum clones were assessed using the SYBR Green I based assay (IC50). For the cytotoxic tests, the LD50 was determined in human pulmonary fibroblast cell line using the [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay. Results: All compounds presented a ligand-receptor interaction with ten Plasmodium falciparum-related protein targets, as well as antimalarial activity against chloroquine resistant strain (IC50 = 3.44 mu M to 19.11 mu M). Three of them (dehydrobufotenine, marinobufagin, and bufalin) showed adequate conditions for oral drug prototypes, with satisfactory prediction of absorption, permeability, and absence of toxicity. In the cell viability assay, only dehydrobufotenin was selective for the parasite. Conclusions: Dehydrobufotenin revealed to be a potential oral drug prototype presenting adequate antimalarial activity and absence of cytotoxicity, therefore should be subjected to further studies.

Acute infection with Plasmodium vivax, classically associated with benign disease, has been presenting as serious and even fatal disease in recent years. Severe disease is mainly due to biochemical and hematological alterations during the acute phase of infection. In the present cross-sectional study, the aspartate aminotransferase-to-platelet ratio index (APRI) was evaluated as a method for identifying patients at risk of severe vivax malaria. This retrospective study included 130 patients with confirmed P. vivax infection between June 2006 and January 2018. Clinical-epidemiological data were obtained from medical records. Hematological and biochemical parameters were determined using automated equipment. The criteria of severity for infection by Plasmodium falciparum, established by the World Health Organization (WHO), were adapted to classify patients with danger signs of severe vivax malaria. Of the 130 patient’s records evaluated, 19 (14.6%) had one or more signs and symptoms of severe malaria. The mean APRI values among patients with and without severe malaria were 2.11 and 1.09, respectively (p = 0.044). Among those with severe disease, the proportion with an APRI value above 1.50 was 30% compared to the 10% among those without severe disease (p = 0.007). The area under the receiver operating characteristic curve (95% CI), calculated to assess the accuracy of the APRI in discriminating between patients with and without severe disease, was 0.645 (0.494; 0.795). An APRI cutoff of 0.74 resulted in sensitivity of 74.0%, specificity of 56.0%, and accuracy of 65.0%. This study shows that the APRI is elevated in patients with evidence of infection by P. vivax. Based on the good sensitivity found in this study, we conclude that this simple index can serve as a diagnostic biomarker to identify patients at risk of severe disease during the acute phase of P. vivax infection.

Plasmodium vivax remains a global health problem and its ability to cause relapses and subpatent infections challenge control and elimination strategies. Even in low malaria transmission settings, such as the Amazon basin, where progress in malaria control has caused a remarkable reduction in case incidence, a recent increase in P. vivax transmission demonstrates the continued vulnerability of P.vivax-exposed populations. As part of a search for complementary approaches to P.vivax surveillance in areas in which adults are the majority of the exposed-population, here we evaluated the potential of serological markers covering a wide range of immunogenicity to estimate malaria transmission trends. For this, antibodies against leading P. vivax blood-stage vaccine candidates were assessed during a 9 year follow-up study among adults exposed to unstable malaria transmission in the Amazon rainforest. Circulating antibody levels against immunogenic P. vivax proteins, such as the Apical Membrane Antigen-1, were a sensitive measure of recent P. vivax exposure, while antibodies against less immunogenic proteins were indicative of naturally-acquired immunity, including the novel engineered Duffy binding protein II immunogen (DEKnull-2). Our results suggest that the robustness of serology to estimate trends in P.vivax malaria transmission will depend on the immunological background of the study population, and that for adult populations exposed to unstable P.vivax malaria transmission, the local heterogeneity of antibody responses should be considered when considering use of serological surveillance.

Malaria has provided a major selective pressure and has modulated the genetic diversity of the human genome. The variants of the Duffy Antigen/Receptor for Chemokines (DARC) gene have probably been selected by malaria parasites, particularly theFY*Oallele, which is fixed in sub-Saharan Africa and confers resistance toPlasmodium vivaxinfection. Here, we showed the influence of genomic ancestry on the distribution of DARC genotypes in a highly admixed Brazilian population and confirmed the decreased susceptibility of theFY*A/FY*Ogenotype to clinicalP. vivaxmalaria.FY*B/FY*Oindividuals were associated with a greater risk of developing clinical malaria. A remarkable difference among DARC variants concerning the susceptibility to clinical malaria was more evident for individuals who were less exposed to malaria, as measured by the time of residence in the endemic area. Additionally, we found that DARC-negative andFY*A/FY*Oindividuals had a greater chance of acquiring high levels of antibodies against the 19-kDa C-terminal region of theP. vivaxmerozoite surface protein-1. Altogether, our results provide evidence that DARC polymorphisms modulate the susceptibility to clinicalP. vivaxmalaria and influence the naturally-acquired humoral immune response to malaria blood antigens, which may interfere with the efficacy of a future vaccine against malaria.