anti-Trypanosoma Cruzi Activity Research Articles

Metallomics: An Essential Tool for the Study of Potential Antiparasitic Metallodrugs.

Metallomics is an emerging area of omics approaches that has grown enormously in the past few years. It integrates research related to metals in biological systems, in symbiosis with genomics and proteomics. These omics approaches can provide in-depth insights into the mechanisms of action of potential metallodrugs, including their physiological metabolism and their molecular targets. Herein, we review the most significant advances concerning cellular uptake and subcellular distribution assays of different potential metallodrugs with activity against Trypanosma cruzi, the protozoan parasite that causes Chagas disease, a pressing health problem in high-poverty areas of Latin America. Furthermore, the first multiomics approaches including metallomics, proteomics, and transcriptomics for the comprehensive study of potential metallodrugs with anti-Trypanosoma cruzi activity are described.

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.

In vitro anti-Trypanosoma cruzi activity of methanolic extract of Bidens pilosa and identification of active compounds by gas chromatography-mass spectrometry analysis.

Chagas disease, caused by Trypanosoma cruzi parasite, is a significant but neglected tropical public health issue in Latin America due to the diversity of its genotypes and pathogenic profiles. This complexity is compounded by the adverse effects of current treatments, underscoring the need for new therapeutic options that employ medicinal plant extracts without negative side effects. Our research aimed to evaluate the trypanocidal activity of Bidens pilosa fractions against epimastigote and trypomastigote stages of T. cruzi, specifically targeting the Brener and Nuevo León strains-the latter isolated from Triatoma gerstaeckeri in General Terán, Nuevo León, México. We processed the plant's aerial parts (stems, leaves, and flowers) to obtain a methanolic extract (Bp-mOH) and fractions with varying solvent polarities. These preparations inhibited more than 90% of growth at concentrations as low as 800 μg/ml for both parasite stages. The median lethal concentration (LC50) values for the Bp-mOH extract and its fractions were below 500 μg/ml. Tests for cytotoxicity using Artemia salina and Vero cells and hemolytic activity assays for the extract and its fractions yielded negative results. The methanol fraction (BPFC3MOH1) exhibited superior inhibitory activity. Its functional groups, identified as phenols, enols, alkaloids, carbohydrates, and proteins, include compounds such as 2-hydroxy-3-methylbenzaldehyde (50.9%), pentadecyl prop-2-enoate (22.1%), and linalool (15.4%). Eight compounds were identified, with a match confirmed by the National Institute of Standards and Technology (NIST-MS) software through mass spectrometry analysis.

Metallomics as an Essential Analytical Tool for the Development of Potential Metallodrugs

Metallomics as an Essential Analytical Tool for the Development of Potential Metallodrugs

Cyclodextrin-encapsulated new drug with promising anti-Trypanosoma cruzi activity

Cyclodextrin-encapsulated new drug with promising anti-Trypanosoma cruzi activity

Piperazine amides with desirable solubility, physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC50 17.8 to 35.9 µM) and no relevant cytotoxicity to mammalian cells (CC50 > 200 µM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antiparasitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.

1,3-Thiazole derivatives as privileged structures for anti-Trypanosoma cruzi activity: Rational design, synthesis, in silico and in vitro studies

Chagas disease is a deadly and centenary neglected disease that is recently surging as a potential global threat. Approximately 30% of infected individuals develop chronic Chagas cardiomyopathy and current treatment with the reference benznidazole (BZN) is ineffective for this stage. We presently report the structural planning, synthesis, characterization, molecular docking prediction, cytotoxicity, in vitro bioactivity and mechanistic studies on the anti-T. cruzi activity of a series of 16 novel 1,3-thiazoles (2–17) derived from thiosemicarbazones (1a, 1b) in a two-step and reproducible Hantzsch-based synthesis approach. The anti-T. cruzi activity was evaluated in vitro against the epimastigote, amastigote and trypomastigote forms of the parasite. In the bioactivity assays, all thiazoles were more potent than BZN against epimastigotes. We found that the compounds presented an overall increased anti-tripomastigote selectivity (Cpd 8 was 24-fold more selective) than BZN, and they mostly presented anti-amastigote activity at very low doses (from 3.65 μM, cpd 15). Mechanistic studies on cell death suggested that the series of 1,3-thiazole compounds herein reported cause parasite cell death through apoptosis, but without compromising the mitochondrial membrane potential. In silico prediction of physicochemical properties and pharmacokinetic parameters showed promising drug-like results, being all the reported compounds in compliance with Lipinski and Veber rules. In summary, our work contributes towards a more rational design of potent and selective antitripanosomal drugs, using affordable methodology to yield industrially viable drug candidates.

Anti-Trypanosoma cruzi activity of Coptis rhizome extract and its constituents

BackgroundCurrent therapeutic agents, including nifurtimox and benznidazole, are not sufficiently effective in the chronic phase of Trypanosoma cruzi infection and are accompanied by various side effects. In this study, 120 kinds of extracts from medicinal herbs used for Kampo formulations and 94 kinds of compounds isolated from medicinal herbs for Kampo formulations were screened for anti-T. cruzi activity in vitro and in vivo.MethodsAs an experimental method, a recombinant protozoan cloned strain expressing luciferase, namely Luc2-Tulahuen, was used in the experiments. The in vitro anti-T. cruzi activity on epimastigote, trypomastigote, and amastigote forms was assessed by measuring luminescence intensity after treatment with the Kampo extracts or compounds. In addition, the cytotoxicity of compounds was tested using mouse and human feeder cell lines. The in vivo anti-T. cruzi activity was measured by a murine acute infection model using intraperitoneal injection of trypomastigotes followed by live bioluminescence imaging.ResultsAs a result, three protoberberine-type alkaloids, namely coptisine chloride, dehydrocorydaline nitrate, and palmatine chloride, showed strong anti-T. cruzi activities with low cytotoxicity. The IC50 values of these compounds differed depending on the side chain, and the most effective compound, coptisine chloride, showed a significant effect in the acute infection model.ConclusionsFor these reasons, coptisine chloride is a hit compound that can be a potential candidate for anti-Chagas disease drugs. In addition, it was expected that there would be room for further improvement by modifying the side chains of the basic skeleton.

Synthetic Analogues of Gibbilimbol B Induce Bioenergetic Damage and Calcium Imbalance in Trypanosoma cruzi

Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series.

Antiparasitic Activity of Hippeastrum Species and Synergistic Interaction between Montanine and Benznidazole against Trypanosoma cruzi.

Hippeastrum species have a wide range of biological properties. In Argentina, this genus comprises ten widely distributed species. To evaluate the antiparasitic and anticholinesterase activities and chemical profiles of seven Argentinean Hippeastrum species and determine the synergism between the major isolated alkaloid-montanine-and benznidazole in anti-Trypanosoma cruzi activity. The antiparasitic activity was evaluated through antiproliferative and viability assays against T. cruzi epimastigotes. Synergism assays were performed using the Chou-Talalay method. AChE and BuChE inhibitory activities were also assessed. The alkaloid composition was obtained using GC-MS analysis. All extracts showed strong growth inhibition of T. cruzi epimastigote proliferation. The extracts from H. aglaiae, H. aulicum, and H. hybrid stand out for their potent and total growth inhibition, which was comparable to benznidazole. The H. reticulatum extract showed strong Acetylcholinesterase (AChE) inhibitory activities, while five species showed moderate Butyrylcholinesterase (BuChE) inhibition. Fifteen alkaloids were identified by means of GC-MS. Regarding the synergism assessment, the highest synergistic effect was obtained from the combination of montanine and benznidazole. Hippeastrum species bulb extracts from Argentina were shown to be a good source of antiparasitic alkaloids and cholinesterase inhibitors. The synergism between montanine and benznidazole emerges as a potential combination for future studies to treat Chagas disease.

New derivatives from dehydrodieugenol B and its methyl ether displayed high anti-Trypanosoma cruzi activity and cause depolarization of the plasma membrane and collapse the mitochondrial membrane potential

In the present work, dehydrodieugenol B (1) and its methyl ether (2), isolated from Nectandra leucantha twigs, were used as starting material for the preparation of two new derivatives (1a and 2a) containing an additional methoxycarbonyl unit on allyl side chains. Compounds 1a and 2a demonstrated activity against trypomastigotes (EC50 values of 13.5 and 23.0 μM, respectively) and against intracellular amastigotes (EC50 values of 10.2 and 6.1 μM, respectively). Additionally, compound 2a demonstrated no mammalian cytotoxicity up to 200 μM whereas compound 1a exhibited a CC50 value of 139.8 μM. The mechanism of action studies of compounds 1a and 2a demonstrated a significant depolarization of the plasma membrane potential in trypomastigotes, followed by a mitochondrial membrane potential collapse. Neither calcium level nor reactive oxygen species alterations were observed after a short-time incubation. Considering the potential of compound 2a against T. cruzi and its simple preparation from the natural product 2, isolated from N. leucantha, this compound could be considered a new hit for future drug design studies in Chagas disease.

Silver Nanoparticles Containing Fucoidan Synthesized by Green Method Have Anti-Trypanosoma cruzi Activity.

The brown seaweed Spatoglossum schröederi synthesizes three bioactive fucoidans, the most abundant of which is fucan A. This fucoidan was extracted and its identity was confirmed by chemical analysis, Fourier-transform infrared spectroscopy (FTIR), and agarose gel electrophoresis. Thereafter, silver nanoparticles containing fucan A (AgFuc) were produced using an environmentally friendly synthesis method. AgFuc synthesis was analyzed via UV–vis spectroscopy and FTIR, which confirmed the presence of both silver and fucan A in the AgFuc product. Dynamic light scattering (DLS), X-ray diffraction, scanning electron microscopy, and atomic force microscopy revealed that the AgFuc particles were ~180.0 nm in size and spherical in shape. DLS further demonstrated that AgFuc was stable for five months. Coupled plasma optical emission spectrometry showed that the AgFuc particles contained 5% silver and 95% sugar. AgFuc was shown to be more effective in inhibiting the ability of parasites to reduce MTT than fucan A or silver, regardless of treatment time. In addition, AgFuc induced the death of ~60% of parasites by necrosis and ~17% by apoptosis. Therefore, AgFuc induces damage to the parasites’ mitochondria, which suggests that it is an anti-Trypanosoma cruzi agent. This is the first study to analyze silver nanoparticles containing fucan as an anti-Trypanosoma cruzi agent. Our data indicate that AgFuc nanoparticles have potential therapeutic applications, which should be determined via preclinical in vitro and in vivo studies.

Oxonitrogenated Derivatives of Eremophilans and Eudesmans: Antiproliferative and Anti-Trypanosoma cruzi Activity.

Cancer is one of the most important causes of death worldwide. Solid tumors represent the vast majority of cancers (>90%), and the chemotherapeutic agents used for their treatment are still characterized by variable efficacy and toxicity. Sesquiterpenes are a group of natural compounds that have shown a wide range of biological activities, including cytotoxic and antiparasitic activity, among others. The antiproliferative activity of natural sesquiterpenes, tessaric acid, ilicic acid, and ilicic alcohol and their semisynthetic derivatives against HeLa, T-47D, WiDr, A549, HBL-100, and SW1573 cell lines were evaluated. The effect of the compounds on Trypanosoma cruzi epimastigotes was also assessed. The selectivity index was calculated using murine splenocytes. Derivatives 13 and 15 were the most antiproliferative compounds, with GI50 values ranging between 5.3 (±0.32) and 14 (±0.90) μM, in all cell lines tested. The presence of 1,2,3-triazole groups in derivatives 15–19 led to improvements in activity compared to those corresponding to the starting natural product (3), with GI50 values ranging between 12 (±1.5) and 17 (±1.1) μM and 16 being the most active compound. In relation to the anti-T. cruzi activity, derivatives 7 and 16 obtained from tessaric acid and ilicic acid were among the most active and selective compounds with IC50 values of 9.3 and 8.8 µM (SI = 8.0 and 9.4), respectively.

A terpenoid-rich extract from Clethra fimbriata exhibits anti-Trypanosoma cruzi activity and induces T cell cytokine production

Chagas disease, a worldwide public health concern, is a chronic infection caused by Trypanosoma cruzi. Considering T. cruzi chronic persistence correlates with CD4+ and CD8+ T cell dysfunction and the safety and efficacy profiles of Benznidazol and Nifurtimox, the two drugs currently used for its etiological treatment, are far from ideal, the search of new trypanocidal treatment options is a highly relevant issue. Therefore, the objective of this work was to evaluate the trypanocidal effect and cytokine production induction of three extracts (hexane, dichloromethane and hydroalcoholic) obtained from Clethra fimbriata, a plant traditionally used as a febrifuge in Colombia. Additionally, the extracts’ major components with the highest trypanocidal activity were determined. It was evidenced C. fimbriata hexane extract exhibited the highest activity capable of inhibiting the three parasite developmental stages with an IC50/EC50 of 153.9 ± 29.5 (epimastigotes), 39.3 ± 7.2 (trypomastigotes), and 45.6 ± 10.5 (amastigotes) μg/mL, presenting a low cytotoxicity in VERO cells with a selectivity index ranging from 6.49 to 25.4. Moreover, this extract induced trypomastigote apoptotic death and inhibited parasite cell infection. The extract also induced IFN-γ and TNF production in CD4+ and CD8+ T cells, as well as de novo production of the cytotoxic molecules granzyme B and perforin in CD8+ T cells from healthy donors. Fatty acids and terpenes represented C. fimbriata key compounds. Thus, the trypanocidal activity and cytokine production induction of the hexane extract may be associated with terpene presence, particularly, triterpenes.

In Vitro Anti-Trypanosoma cruzi Activity of Halophytes from Southern Portugal Reloaded: A Special Focus on Sea Fennel (Crithmum maritimum L.)

Marine halophytes are an outstanding reservoir of natural products and several species have anti-infectious traditional uses. However, reports about their potential use against neglected tropical ailments, such as Chagas disease, are scarce. This work evaluated for the first time the in vitro anti-Trypanosoma cruzi activity of extracts from the aromatic and medicinal species Helichrysum italicum subsp. picardii (Boiss. & Reut.) Franco (Asteraceae, everlasting) and Crithmum maritimum L. (Apiaceae, sea fennel). For that purpose, decoctions, tinctures, and essential oils from everlasting’s flowers and sea fennel’s stems, leaves, and flowers were tested against intracellular amastigotes of two T. cruzi strains. The extract from the sea fennel flower decoction displayed significant anti-trypanosomal activity and no toxicity towards the host cell (EC50 = 17.7 µg/mL, selectivity index > 5.65). Subsequent fractionation of this extract afforded 5 fractions that were re-tested in the same model of anti-parasitic activity. Fraction 1 was the most active and selective (EC50 = 0.47 μg/mL, selectivity index = 59.6) and was submitted to preparative thin-layer chromatography. One major compound was identified, falcarindiol, which was likely the one responsible for the observed anti-trypanosomal activity. This was confirmed using a commercially sourced molecule. Target-fishing studies showed falcarindiol as a ligand of T. cruzi spermidine synthase, pointing to a potential enzyme-inhibiting anti-trypanosomal mechanism of action. Overall, this work shows that sea fennel can provide effective anti-parasitic molecule(s) with potential pharmacological applications in the treatment of CD.

In Vitro Phenotypic Activity and In Silico Analysis of Natural Products from Brazilian Biodiversity on Trypanosoma cruzi.

Chagas disease (CD) affects more than 6 million people worldwide. The available treatment is far from ideal, creating a demand for new alternative therapies. Botanical diversity provides a wide range of novel potential therapeutic scaffolds. Presently, our aim was to evaluate the mammalian host toxicity and anti-Trypanosoma cruzi activity of botanic natural products including extracts, fractions and purified compounds obtained from Brazilian flora. In this study, 36 samples of extracts and fractions and eight pure compounds obtained from seven plant species were evaluated. The fraction dichloromethane from Aureliana fasciculata var. fasciculata (AFfPD) and the crude extract of Piper tectoniifolium (PTFrE) showed promising trypanosomicidal activity. AFfPD and PTFrE presented EC50 values 10.7 ± 2.8 μg/mL and 12.85 ± 1.52 μg/mL against intracellular forms (Tulahuen strain), respectively. Additionally, both were active upon bloodstream trypomastigotes (Y strain), exhibiting EC50 2.2 ± 1.0 μg/mL and 38.8 ± 2.1 μg/mL for AFfPD and PTFrE, respectively. Importantly, AFfPD is about five-fold more potent than Benznidazole (Bz), the reference drug for CD, also reaching lower EC90 value (7.92 ± 2.2 μg/mL) as compared to Bz (23.3 ± 0.6 μg/mL). Besides, anti-parasitic effect of eight purified botanic substances was also investigated. Aurelianolide A and B (compounds 1 and 2) from A. fasciculata and compound 8 from P. tuberculatum displayed the best trypanosomicidal effect. Compounds 1, 2 and 8 showed EC50 of 4.6 ± 1.3 μM, 1.6 ± 0.4 μM and 8.1 ± 0.9 μM, respectively against intracellular forms. In addition, in silico analysis of these three biomolecules was performed to predict parameters of absorption, distribution, metabolism and excretion. The studied compounds presented similar ADMET profile as Bz, without presenting mutagenicity and hepatotoxicity aspects as predicted for Bz. Our findings indicate that these natural products have promising anti-T. cruzi effect and may represent new scaffolds for future lead optimization.

Plinia cauliflora (Mart.) Kausel (Jaboticaba) leaf extract: In vitro anti-Trypanosoma cruzi activity, toxicity assessment and phenolic-targeted UPLC-MSE metabolomic analysis

Ethnopharmacological relevancePlinia cauliflora (Mart.) Kausel, known as Brazilian grape or jaboticaba, is widely used in Brazilian traditional medicine to treat infectious and inflammatory disorders. However, several aspects of its biological potential remain unclear, such as toxicity and effects on pathogenic protozoa. Aim of the studyInvestigate the phenolic composition, the in vitro and in silico toxicity profile, and the anti-Trypanosoma cruzi activity of the phenolics-enriched hydromethanolic extract of P. cauliflora leaf. Material and methodsPhytochemical analysis was performed ultra-performance liquid chromatography-mass spectrometry (UPLC-MSE). Mutagenicity, genotoxicity and eukaryotic cytotoxicity was evaluated by Ames test, cytokinesis-block micronucleus and colorimetric assays, respectively, alongside with a computational prediction of the major compound's pharmacokinetics and toxicity. Anti-T. cruzi activity was investigated on T. cruzi bloodstream trypomastigotes. ResultsA total of 14 phenolic compounds were identified, including 11 flavonoids and 2 phenolic acids. No positive response regarding mutagenic potential was detected in Salmonella strains TA97, TA98, TA100, TA102, TA104, both in absence or presence of metabolic activation. The extract induced significant dose-response reduction on nuclear division indexes of HepG2 cells, suggesting cytostatic effects, with no micronuclei induction on cytokinesis-block micronucleus assay. Likewise, it also presented cytotoxic effects, inducing HepG2 and F C3H dose and time dependently cell death through cell membrane damage and more evidently by mitochondrial dysfunction. A dose-response curve of in vitro trypanocidal activity was observed against T. cruzi bloodstream trypomastigotes after 2 and 24 h of exposure. In silico predictions of most abundant compounds' structural alerts, pharmacokinetics and toxicity profile indicates a moderately feasible druglikeness profile and low toxicity for them, which is compatible with in vitro results. ConclusionsThe present study demonstrated that P. cauliflora leaf extract is a potential source of antiparasitic bioactive compounds, however it presents cytotoxic effects in liver cell lines.

Anti-Trypanosoma cruzi activity, cytotoxicity, and chemical characterization of extracts from seeds of Lonchocarpus cultratus.

Trypanosoma cruzi is the agent of Chagas' disease and affects approximately 6-8 million people worldwide. The search for new anti-T. cruzi drugs are relevant because only two drugs exist actually. The objective of this study was to investigate the effect of the extracts from the seeds of Lonchocarpus cultratus on T. cruzi, its cytotoxicity as well as to elucidate its chemical profile. The characterization of the extracts was done using 1H-RMN. T. cruzi forms were treated with increasing concentrations of the extracts and after, the percentage of inhibition and IC50 or LC50 were calculated. Murine peritoneal macrophages were treated with different concentrations of the extracts to evaluate the cellular viability. The hemotoxicity was accessed by verifying the levels of hemolysis caused by the extracts on human red blood cells. Chalcones isocordoin and lonchocarpin were detected in the dichloromethane extract, and chalcone lonchocarpin was detected in the hexane extract. The dichloromethane extract showed higher activity against all the forms of T. cruzi compared to the other two extracts, but the hexane showed the best selectivity index. The cytotoxicity observed in murine macrophages was confirmed in human erythrocytes, with dichloromethane extract having the highest toxicity. The methanolic extract showed the lowest anti-T. cruzi activity but was nontoxic to peritoneal murine macrophages and red blood cells. L. cultratus extracts have the potential to be explored for the development of new anti-trypanosomal drugs. This study was the first to demonstrate the action of extracts from the genus Lonchocarpus on infecting forms of T. cruzi.

Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds.

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. T. cruzi modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti-T. cruzi activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC50 = 0.27 μmol L−1) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind T. cruzi Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic T. cruzi infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.

MOLECULAR DEREPLICATION OF VOLATILE OILS FROM Saururus cernuus L. AND EVALUATION OF ANTITrypanosoma cruzi ACTIVITY

The present study reports the molecular dereplication and the evaluation of anti-Trypanosoma cruzi activity of volatile oils from inflorescences, leaves, branches, and roots of Saururus cernuus L. (Saururaceae). Chemically, the oils showed the predominance of sesquiterpenes in inflorescences (64.04%) and branches (63.82%), with b-sesquiphellandrene (25.50%) and (E)-caryophyllene (22.40%) corresponding to the main constituents of each oil. Furthermore, it was possible to detect safrole as the most predominant compound in the leaves oil (49.09%). On the other hand, the oil from roots was mainly composed by monoterpenes (84.60%), with limonene in higher concentration (38.41%), followed by α-pinene (20.19%), and camphene (14.71%). The oils from inflorescences and branches displayed higher antitrypanosomal potency with EC50 values of 7.1 and 8.8 μg mL-1, respectively, followed by the oils from the roots and inflorescences, with EC50 values of 17.3 and 30.4 μg mL-1, respectively. Additionally, branches and inflorescences oils displayed no toxicity in mammalian NCTC cells (CC50 > 200 μg mL-1). Using two PLS-DA methods, it was possible to suggest that the anti-T. cruzi activity of the tested oils could be associated with the presence of β-sesquiphellandrene, safrole, β-elemene, and α-zingiberene whereas threo-austrobailignan-5, β-sesquiphellandrene, α-humulene, germacrene D, and bicyclogermacrene play a role in the cytotoxicity against NCTC cells.