Exploring Quinazoline Nitro-Derivatives as Potential Antichagasic Agents: Synthesis and In Vitro Evaluation.

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in humans. The current antichagasic drugs nifurtimox and benznidazole have inconveniences of toxicity; therefore, the search for alternative therapeutic strategies is necessary. The present study reports the synthesis, drug-likeness predictions, and in vitro anti-trypanosome activity of a series of 14 quinazoline 2,4,6-triamine derivatives. All compounds were tested against T. cruzi (epimastigotes and trypomastigotes) and in HFF1 human foreskin fibroblasts. The bioassays showed that compounds 2-4 containing nitrobenzoyl substituents at 6-position of the quinazoline 2,4,6-triamine nucleus were the most potent on its antiprotozoal activity. The effect was observed at 24 h and it was preserved for at least 5 days. Also, compounds 2-4 were not toxic to the human control cells, showing high selectivity index. The quinazoline nitro derivatives have potential use as antichagasic agents.

Cyclodextrin Complexes for the Treatment of Chagas Disease: A Literature Review.

Cyclodextrins are ring-shaped sugars used as additives in medications to improve solubility, stability, and sensory characteristics. Despite being widespread, Chagas disease is neglected because of the limitations of available medications. This study aims to review the compounds used in the formation of inclusion complexes for the treatment of Chagas disease, analyzing the incorporated compounds and advancements in related studies. The databases consulted include Scielo, Scopus, ScienceDirect, PubMed, LILACS, and Embase. The keywords used were "cyclodextrin AND Chagas AND disease" and "cyclodextrin complex against Trypanosoma cruzi". Additionally, a statistical analysis of studies on Chagas disease over the last five years was conducted, highlighting the importance of research in this area. This review focused on articles that emphasize how cyclodextrins can improve the bioavailability, therapeutic action, toxicity, and solubility of medications. Initially, 380 articles were identified with the keyword "cyclodextrin AND Chagas disease"; 356 were excluded for not being directly related to the topic, using the keyword "cyclodextrin complex against Trypanosoma cruzi". Over the last five years, a total of 13,075 studies on Chagas disease treatment were found in our literature analysis. The studies also showed interest in molecules derived from natural products and vegetable oils. Research on cyclodextrins, particularly in the context of Chagas disease treatment, has advanced significantly, with studies highlighting the efficacy of molecules in cyclodextrin complexes and indicating promising advances in disease treatment.

Dissimilar Trypanosoma cruzi genotype-specific serological profile assessed by Chagas-Flow ATE IgG1 upon benznidazole etiological treatment of chronic Chagas disease.

The present study aimed to verify the impact of etiological treatment on the genotype-specific serological diagnosis of chronic Chagas disease patients (CH), using the Chagas-Flow ATE IgG1 methodology. For this purpose, a total of 92 serum samples from CH, categorized as Not Treated (NT, n = 32) and Benznidazole-Treated (Bz-T, n = 60), were tested at Study Baseline and 5Years Follow-up. At Study Baseline, all patients have the diagnosis of Chagas disease confirmed by Chagas-Flow ATE IgG1, using the set of attributes ("antigen/serum dilution/cut-off"; "EVI/250/30%"). The genotype-specific serodiagnosis at Study Baseline demonstrated that 96% of patients (44/46) presented a serological profile compatible with TcII genotype infection. At 5Years Follow-up monitoring, NT and Bz-T presented no changes in anti-EVI IgG1 reactivity. However, significant differences were detected in the genotype-specific IgG1 reactivity for Bz-T. The most outstanding shift comprised the anti-amastigote TcVI/(AVI), anti-amastigote TcII/(AII) and anti-epimastigote TcVI/(EVI) reactivities. Regardless no changes in the genotype-specific serology of NT (TcI = 6%; TcII = 94%), distinct T. cruzi genotype-specific sero-classification was detected for Bz-T samples at 5Years Follow-up (TcII = 100%) as compared to Baseline (TcII = 97%; TcVI = 3%). The anti-trypomastigote TcI/(TI) was the attribute accountable for the change in genotype-specific sero-classification. In conclusion, our findings of dissimilar T. cruzi genotype-specific serology upon Bz-treatment re-emphasize the relevance of accomplishing the genotype-specific serodiagnosis during clinical pos-therapeutic management of chronic Chagas disease patients.

Euphane and Tirucallane Triterpenes with Trypanocidal Activity from Euphorbia desmondii.

The phytochemical investigation of Euphorbia desmondii resulted in the isolation of 15 previously undescribed triterpenoids (desmondiins A, C-P) and 8 already described compounds. The structures of the isolated compounds were determined by extensive spectroscopic analyses. The compounds were identified as tirucallane and euphane triterpenes based on 7-keto-8-ene, 11-keto-8-ene, or 7,11-diketo-8-ene skeletons. Additionally, the selective trypanocidal activities of these compounds against Trypanosoma cruzi were evaluated. Desmondiins A, C, D, F, H, and M exhibited IC50 values in the range of 3-5 µM, and selectivity indices between 5-9, against T. cruzi epimastigotes over the host cell (RAW264.7 macrophages). Furthermore, desmondiin A efficiently inhibited amastigote replication in host cells (IC50 = 2.5 ± 0.3 µM), which was comparable to that of the positive control, benznidazole (3.6 ± 0.4 µM). Overall, the isolated euphane and tirucallane triterpenoids could act as antichagasic lead scaffolds.

Congenital transmission of Chagas disease: The role of newborn therapy on the disease's dynamics.

Chagas disease, also known as American trypanosomiasis, is caused by a protozoan blood-borne pathogen called Trypanosoma cruzi. The World Health Organization (WHO) has classified Chagas as one of 21 neglected tropical diseases present in the world and estimates that 6-7 million people are currently infected with Chagas. Congenital transmission of Chagas disease contributes to a significant amount of new infections, especially in endemic areas where 22.5% of new infections are due to congenital transmission. In this paper, we investigate congenital transmission's impact on Chagas disease dynamics through a mathematical model. Specifically, we examine how treating a proportion of infants born to infected individuals impacts the progression and spread of Chagas disease. The influence of newborn therapy on the dynamics of the model is thoroughly investigated, both theoretically and numerically. The results illustrate the importance of treating a high proportion of newborns to reduce the number of infected cases of the disease. The findings show that the therapy given to newborns is necessary but not sufficient to curb the transmission of Chagas disease, and a comprehensive approach that includes vector and vertical transmission control strategies is essential for eradicating Chagas disease. We also observed that if vector transmission can be controlled, then at least 55% of the newborns need to be treated to eliminate the disease.

Quality, supply chain, and use of Trypanocidal drugs among camel keepers in north-eastern Kenya: A cross-sectional study.

The non-cyclic trypanosomiasis (surra), caused by Trypanosoma evansi, and mechanically transmitted by biting flies, hinders camel productivity in Kenya. Trypanocides are the most commonly used drugs to control surra. However, emergence of drug resistance by the parasites is a major limitation to control efforts. There is limited information on the quality of trypanocides, the supply chain and drug-use practices among camel keepers potentially contributing to development of drug resistance in Kenya. We sought to fill this gap by conducting a cross-sectional study among camel keepers in Isiolo and Marsabit counties, Kenya. We mapped the trypanocide drugs supply chain through quantitative and qualitative surveys. We administered a semi-structured questionnaire to camel keepers to generate data on trypanocides-use practices, including the types, sources, person who administers treatment, reconstitution, dosage, route and frequency of administration, among others. Additionally, we tested the quality of trypanocidal drugs retailed in the region. We mapped a total of 55 and 49 agro-veterinary outlets and general (ordinary) shops retailing veterinary drugs in the two counties, respectively. These comprised of 29 and 26 agro-veterinary outlets, as well as 24 and 25 general shops in Isiolo and Marsabit counties, respectively. Overall, the respondents experienced 283 surra cases in the three-month recall period, which were treated with trypanocides. The majority of these cases were diagnosed by camel owners (71.7%) and herders (24.1%). A significant proportion of the cases were treated by camel owners (54.8%), herders (35.3%), the owner's son (3.2%) and veterinary personnel (1.1%) (χ2 = 24.99, p = 0.000). Most of the households sourced the drugs from agro-veterinary outlets (59.0%), followed by general shops (19.8%), veterinary personnel (2.1%), and open-air markets (0.4%) (χ2 = 319.24, p = 0.000). Quinapyramine was the most (56.9%) predominantly used trypanocide in treatment of surra, followed by homidium (19.8%), isometamidium (15.9%), diminazene aceturate (6.7%), and ethidium (0.7%) (χ2 = 340.75, p < 0.000). Only a meager proportion of respondents (15.2%) used the drugs correctly as instructed by the manufacturers. We recorded an association between correct drug usage, with the person who administers the treatment (χ2 = 17.7, p = 0.003), and the type of trypanocide used (χ2 = 19.4, p < 0.001). All the drug samples tested had correct concentrations of active ingredient (100.0%), and therefore of good quality. We have demonstrated that whereas the trypanocides retailed in the region by authorized vendors are of good quality, there is widespread incorrect handling and use of the drugs by unqualified individuals, which may contribute to treatment failure and emergence of trypanocide resistance.

Causality and Severity of Adverse Reactions and Biochemical Changes to Benznidazole Treatment in Patients with Chronic Chagas Disease. / Causalidade e Gravidade das Reações Adversas e Alterações Laboratoriais ao Tratamento com Benznidazol em Pacientes com Doença de Chagas Crônica.

BACKGROUND: Chagas disease (CD) is a serious public health problem in Latin America. Benznidazole (BNZ) is used for the treatment of CD and, despite its wide use, little information is available about its toxicity and mechanisms of adverse drug reactions (ADR). OBJECTIVES: To identify and classify clinical and laboratory adverse reactions caused by BNZ in terms of causality and severity. METHODS: Prospective cohort study from January 2018 to December 2021. Treatment follow-up included visits and biochemical tests (complete blood count, liver and kidney function tests) before, during and after treatment. ADR were classified according to causality and severity. In the statistical analysis, the significance level was set at p<0.05. RESULTS: Forty patients with chronic CD were included. A high prevalence of ADR was observed 161 ADR in 30 patients [90%]; of these, 104 (64.6%) were classified as possible and 57 (35.4%) as probable. The ADR were classified as moderate and mild. Of the 40 patients, nine (22.5%) discontinued treatment. ADR associated with treatment discontinuation and interventions were those that affected the dermatological system, central and peripheral nervous system and sense organs such as ageusia. Mild hematological and biochemical changes such as lymphopenia were observed after 30 days of treatment. CONCLUSION: Many patients were able to complete the treatment even with ADR, which can be attributed to the successful follow-up strategy with symptomatic treatment and counseling, leading to patient's awareness of symptoms and treatment adherence.

FUNDAMENTO: A Doença de Chagas (DC) representa um grave problema de saúde pública na América Latina. O Benznidazol (BNZ) é utilizado para o tratamento DC e, apesar do seu amplo uso, poucas informações estão disponíveis sobre sua toxicidade e mecanismos das Reações Adversas ao Medicamento (RAM). OBJETIVOS: Identificar e classificar as reações adversas clínicas e laboratoriais ocasionadas pelo uso do BNZ quanto à sua causalidade e gravidade. MÉTODOS: Estudo de coorte prospectivo realizado no período de janeiro de 2018 a dezembro de 2021. O acompanhamento do tratamento incluiu consultas e análises laboratoriais antes, 30 e 60 dias após o início do tratamento. As RAM foram classificadas quanto à causalidade e gravidade. Na análise estatística o nível de significância adotado foi p<0,05. RESULTADOS: Participaram do estudo 40 pacientes com DC crônica, observou-se alta prevalência de RAM com um total de 161 em 30 (90%) pacientes. Destas, 104 (64,6%) foram classificadas como possíveis e 57 (35,4%) como prováveis. As reações foram classificadas em moderadas e leves. Dos 40 pacientes, nove (22,5%) suspenderam o tratamento. As RAM associadas à interrupção e intervenções foram as que afetaram o sistema dermatológico, sistema nervoso central e periférico ou que culminaram em ageusia. Após 30 dias de tratamento, alterações hematológicas e bioquímicas leves foram observadas como linfopenia. CONCLUSÃO: Apesar do elevado percentual de RAM, muitos pacientes foram capazes de completar o tratamento, o que se atribui ao êxito da estratégia de acompanhamento com intervenções de tratamento sintomático juntamente ao aconselhamento, levando à compreensão da sintomatologia e manutenção do tratamento.

Prevention of congenital chagas disease by trypanocide treatment in women of reproductive age: A meta-analysis of observational studies.

BACKGROUND: Maternal-foetal transmission of Chagas disease (CD) affects newborns worldwide. Although Benznidazole and Nifurtimox therapies are the standard treatments, their use during pregnancy is contra-indicated. The effectiveness of trypanocidal medications in preventing congenital Chagas Disease (cCD) in the offsprings of women diagnosed with CD was highly suggested by other studies. METHODS: We performed a systematic review and meta-analysis of studies evaluating the effectiveness of treatment for CD in women of childbearing age and reporting frequencies of cCD in their children. PubMed, Scopus, Web of Science, Cochrane Library, and LILACS databases were systematically searched. Statistical analysis was performed using Rstudio 4.2 using DerSimonian and Laird random-effects models. Heterogeneity was examined with the Cochran Q test and I2 statistics. A p-value of <0.05 was considered statistically significant. RESULTS: Six studies were included, comprising 744 children, of whom 286 (38.4%) were born from women previously treated with Benznidazole or Nifurtimox, trypanocidal agents. The primary outcome of the proportion of children who were seropositive for cCD, confirmed by serology, was signigicantly lower among women who were previously treated with no congenital transmission registered (OR 0.05; 95% Cl 0.01-0.27; p = 0.000432; I2 = 0%). In women previously treated with trypanocidal drugs, the pooled prevalence of cCD was 0.0% (95% Cl 0-0.91%; I2 = 0%), our meta-analysis confirms the excellent effectiveness of this treatment. The prevalence of adverse events in women previously treated with antitrypanocidal therapies was 14.01% (95% CI 1.87-26.14%; I2 = 80%), Benznidazole had a higher incidence of side effects than Nifurtimox (76% vs 24%). CONCLUSION: The use of trypanocidal therapy in women at reproductive age with CD is an effective strategy for the prevention of cCD, with a complete elimination of congenital transmission of Trypanosoma cruzi in treated vs untreated infected women.

Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain.

Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.

In Vitro and In Silico Evaluation of the Leishmanicidal and Trypanocidal Activities of Lignan Methylpiperitol Isolated from Persea Fulva.

Neglected Tropical Diseases are a significant concern as they encompass various infections caused by pathogens prevalent in tropical regions. The limited and often highly toxic treatment options for these diseases necessitate the exploration of new therapeutic candidates. In the present study, the lignan methylpiperitol was isolated after several chromatographic steps from Persea fulva L. E. Koop (Lauraceae) and its leishmanicidal and trypanocidal activities were evaluated using in vitro and in silico approaches. The chemical structure of methylpiperitol was defined by NMR and MS spectral data analysis. The antiprotozoal activity of methylpiperitol was determined in vitro and indicated potency against trypomastigote forms of Trypanosoma cruzi (EC50 of 4.5±1.1 mM) and amastigote forms of Leishmania infantum (EC50 of 4.1±0.5 mM), with no mammalian cytotoxicity against NCTC cells (CC50>200 mM). Molecular docking studies were conducted using six T. cruzi and four Leishmania. The results indicate that for the molecular target hypoxanthine phosphoribosyl transferase in T. cruzi and piteridine reductase 1 of L. infatum, the methylpiperitol obtained better results than the crystallographic ligand. Therefore, the lignan methylpiperitol, isolated from P. fulva holds potential for the development of new prototypes for the treatment of Neglected Tropical Diseases, especially leishmaniasis.

Impact of gastrointestinal inoculation and benznidazole treatment on infection by Trypanosoma cruzi (Y strain, DTU TcII) in Swiss mice.

In Brazil, where Chagas disease is endemic, the most frequent form of transmission of the parasite is the oral route, associated with greater severity and worse response to benznidazole (BZ), the drug used in its treatment. This study aimed to evaluate the impact of gastrointestinal infection (GI) and BZ treatment on the parasitological and histopathological parameters in mice inoculated with a strain of T. cruzi II. Swiss mice were inoculated by GI and intraperitoneal (IP) routes with 2x106 culture-derived metacyclic trypomastigotes of the Y strain (TcII) of T. cruzi and were treated with BZ in the acute phase of the infection. Fresh blood examination, qPCR, histopathological and biochemical evaluations (enzymatic dosages and oxidative stress-OS) were performed. BZ treatment of uninfected animals caused changes in the liver, increased the activity of aspartate aminotransferase and alanine aminotransferase enzymes and OS, showing that the drug alone affects this organ. Inflammation and necrosis in the cardiac tissue were less intense and deaths occurred later in animals inoculated via the GI route than the animals inoculated via the IP route. BZ reduced the intensity of tissue lesions and avoided lethality in animals inoculated via the GI route, and decreased parasitemia and OS in those inoculated via both routes. Although BZ alone caused liver damage, it was less intense than that caused by both routes of inoculation. Infection with the Y strain of T. cruzi II via the GI route proved to be less virulent and pathogenic and responded better to treatment than the infection acquired via the IP route.

Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents.

American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6-7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients' treatment abandonment. Therefore, there is a need for new and better treatments. In this work, the molecular docking of nine hundred twenty-four FDA-approved drugs on three different sites of trypanothione reductase of T. cruzi (TcTR) was carried out to find potential trypanocidal agents. Finally, biological evaluations in vitro and in vivo were conducted with the selected FDA-approved drugs. Digoxin, alendronate, flucytosine, and dihydroergotamine showed better trypanocidal activity than the reference drugs benznidazole and nifurtimox in the in vitro evaluation against the trypomastigotes form. Further, these FDA-approved drugs were able to reduce 20-50% parasitemia in a short time in an in vivo model, although with less efficiency than benznidazole. Therefore, the results suggest a combined therapy of repurposed and canonical drugs against T. cruzi infection.

Pilot-Scale Screening of Clinically Approved Drugs to Identify Uridine Insertion/Deletion RNA Editing Inhibitors in Trypanosoma brucei.

RNA editing pathway is a validated target in kinetoplastid parasites (Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp.) that cause severe diseases in humans and livestock. An essential large protein complex, the editosome, mediates uridine insertion and deletion in RNA editing through a stepwise process. This study details the discovery of editosome inhibitors by screening a library of widely used human drugs using our previously developed in vitro biochemical Ribozyme Insertion Deletion Editing (RIDE) assay. Subsequent studies on the mode of action of the identified hits and hit expansion efforts unveiled compounds that interfere with RNA-editosome interactions and novel ligase inhibitors with IC50 values in the low micromolar range. Docking studies on the ligase demonstrated similar binding characteristics for ATP and our novel epigallocatechin gallate inhibitor. The inhibitors demonstrated potent trypanocidal activity and are promising candidates for drug repurposing due to their lack of cytotoxic effects. Further studies are necessary to validate these targets using more definitive gene-editing techniques and to enhance the safety profile.

Pemuchiamides A and B, Proline-Rich Linear Lipopeptides, Isolated from a Marine Hormoscilla sp. Cyanobacterium.

Pemuchiamides A and B (1 and 2) were isolated from a marine Hormoscilla sp. cyanobacterium collected from Pemuchi Beach on Hateruma Island, Japan. Although 1 and 2 existed as a complex mixture of rotamers in chloroform-d, detailed analyses of their 2D NMR and tandem mass spectra revealed their planar structures, respectively. The absolute configurations of 1 and 2 were established via the degradation and derivatization reactions. Pemuchiamide A (1) exhibited potent growth-inhibitory activity against Trypanosoma brucei rhodesiense, the causative organism of African sleeping sickness, while 2 showed 10-fold weaker activity than 1. This result indicates that the presence of a hydroxy group at the C-3 position of the 4-aminobutanoic acid moiety negatively affects antitrypanosomal activity.

Organic solvent-free benznidazole nanosuspension as an approach to a novel pediatric formulation for Chagas disease.

Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.

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Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds.

Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.

New insights into the pro-oxidant mechanism of dehydroleucodine on Trypanosoma cruzi.

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, 1H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.

Potential anti-HIV and antitrypanosomal components revealed in Sorindeia nitidula via LC-ESI-QTOF-MS/MS.

Sorindeia nitidula (Anacardiaceae) is used by traditional practitioners to treat influenza illnesses with cephalgia and febrile aches. However, the potential active ingredients for its remarkable antioxidant, anti-HIV and antitrypanosomal activities remain unexplored. The present study aims to evaluate the antioxidant, anti-HIV and antitrypanosomal activities of the ethyl acetate extract of S. nitidula (SN) in order to screen out the bioactive compounds and to analyze their possible mechanisms of action. Overall, 21 phenolic compounds were annotated, by using the MS and MS/MS information provided by the QTOF-MS. In vitro assays on the extract revealed potent antioxidant (IC50 = 0.0129 ± 0.0001 mg/mL), anti-HIV (IC50 = 1.736 ± 0.036 µM), antitrypanosomal (IC50 = 1.040 ± 0.010 µM) activities. Furthermore, SN did not present cytotoxic effect on HeLa cancer cell lines. The integrated strategy based on LC-ESI-QTOF-MS/MS provided a powerful tool and a multidimensional perspective for further exploration of active ingredients in S. nitidula responsible for the antioxidant, anti-HIV and antitrypanosomal activities.