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1.
Front Cell Infect Microbiol ; 12: 944748, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909956

RESUMO

Chagas disease is a devastating neglected disease caused by the parasite Trypanosoma cruzi, which affects millions of people worldwide. The two anti-parasitic drugs available, nifurtimox and benznidazole, have a good efficacy against the acute stage of the infection. But this is short, usually asymptomatic and often goes undiagnosed. Access to treatment is mostly achieved during the chronic stage, when the cardiac and/or digestive life-threatening symptoms manifest. Then, the efficacy of both drugs is diminished, and their long administration regimens involve frequently associated adverse effects that compromise treatment compliance. Therefore, the discovery of safer and more effective drugs is an urgent need. Despite its advantages over lately used phenotypic screening, target-based identification of new anti-parasitic molecules has been hampered by incomplete annotation and lack of structures of the parasite protein space. Presently, the AlphaFold Protein Structure Database is home to 19,036 protein models from T. cruzi, which could hold the key to not only describe new therapeutic approaches, but also shed light on molecular mechanisms of action for known compounds. In this proof-of-concept study, we screened the AlphaFold T. cruzi set of predicted protein models to find prospective targets for a pre-selected list of compounds with known anti-trypanosomal activity using docking-based inverse virtual screening. The best receptors (targets) for the most promising ligands were analyzed in detail to address molecular interactions and potential drugs' mode of action. The results provide insight into the mechanisms of action of the compounds and their targets, and pave the way for new strategies to finding novel compounds or optimize already existing ones.


Assuntos
Doença de Chagas , Parasitos , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Preparações Farmacêuticas , Tripanossomicidas/química , Tripanossomicidas/farmacologia
2.
Front Cell Infect Microbiol ; 12: 855119, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35865815

RESUMO

Drug repurposing and combination therapy have been proposed as cost-effective strategies to improve Chagas disease treatment. Miltefosine (MLT), a synthetic alkylphospholipid initially developed for breast cancer and repositioned for leishmaniasis, is a promising candidate against Trypanosoma cruzi infection. This study evaluates the efficacy of MLT as a monodrug and combined with benznidazole (BZ) in both in vitro and in vivo models of infection with T. cruzi (VD strain, DTU TcVI). MLT exhibited in vitro activity on amastigotes and trypomastigotes with values of IC50 = 0.51 µM (0.48 µM; 0,55 µM) and LC50 = 31.17 µM (29.56 µM; 32.87 µM), respectively. Drug interaction was studied with the fixed-ration method. The sum of the fractional inhibitory concentrations (ΣFICs) resulted in ∑FIC= 0.45 for trypomastigotes and ∑FIC= 0.71 for amastigotes, suggesting in vitro synergistic and additive effects, respectively. No cytotoxic effects on host cells were observed. MLT efficacy was also evaluated in a murine model of acute infection alone or combined with BZ. Treatment was well tolerated with few adverse effects, and all treated animals displayed significantly lower mean peak parasitemia and mortality than infected non-treated controls (p<0.05). The in vivo studies showed that MLT led to a dose-dependent parasitostatic effect as monotherapy which could be improved by combining with BZ, preventing parasitemia rebound after a stringent immunosuppression protocol. These results support MLT activity in clinically relevant stages from T. cruzi, and it is the first report of positive interaction with BZ, providing further support for evaluating combined schemes using MLT and exploring synthetic alkylphospholipids as drug candidates.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nitroimidazóis , Parasitemia/tratamento farmacológico , Fosforilcolina/análogos & derivados , Tripanossomicidas/farmacologia
4.
Pharm Pat Anal ; 11(3): 97-110, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35861035

RESUMO

American trypanosomiasis is a neglected tropical disease and an endemic problem in 21 Latin American countries, whose treatment relies on only two US FDA-approved drugs: benznidazole and nifurtimox. Patent literature reveals vital information on new trends in therapies for various diseases, including Chagas disease. The authors used the patent databases of the world's major patent offices to generate an overview of patent trends related to the treatment of Chagas disease. A total of 50 patent families were collected and grouped as 'small molecules', 'pharmaceutical compositions of known compounds' and vaccines. From the results and interpretation, it can be concluded that the treatment of Chagas disease receives little attention in the field of patents and that the upward trend is minimal.


Assuntos
Doença de Chagas , Tripanossomicidas , Doença de Chagas/tratamento farmacológico , Doença de Chagas/epidemiologia , Humanos , Doenças Negligenciadas/tratamento farmacológico , Nifurtimox/uso terapêutico , Preparações Farmacêuticas , Tripanossomicidas/uso terapêutico
5.
Acta Trop ; 233: 106547, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35667455

RESUMO

Current treatment for Chagas disease is based on only two drugs: benznidazole and nifurtimox. Compounds containing sulfur (S) in their structure have shown promising results in vitro and in vivo against Trypanosoma cruzi, the parasite causing Chagas disease. Notably, some reports show that the isosteric replacement of S by selenium (Se) could be an interesting strategy for the development of new compounds for the treatment of Chagas disease. To date, the activity against T. cruzi of three Se- containing groups has been compared with their S counterparts: selenosemicarbazones, selenoquinones, and selenocyanates. More studies are needed to confirm the positive results of Se compounds. Therefore, we have investigated S compounds described in the literature tested against T. cruzi. We focused on those tested in vivo that allowed isosteric replacement to propose their Se counterparts as promising compounds for the future development of new drugs against Chagas disease.


Assuntos
Doença de Chagas , Selênio , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Selênio/uso terapêutico , Enxofre/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
6.
Artigo em Inglês | MEDLINE | ID: mdl-35772309

RESUMO

In addition to the long-established role in erythropoiesis, erythropoietin (Epo) has protective functions in a variety of tissues, including the heart. This is the most affected organ in chronic Chagas disease, caused by the protozoan Trypanosoma cruzi. Despite seven million people being infected with T. cruzi worldwide, there is no effective treatment preventing the disease progression to the chronic phase when the pathological involvement of the heart is often observed. Chronic chagasic cardiomyopathy has a wide variety of manifestations, like left ventricular systolic dysfunction, dilated cardiomyopathy, and heart failure. Since Epo may help maintain cardiac function by reducing myocardial necrosis, inflammation, and fibrosis, this study aimed to evaluate whether the Epo has positive effects on experimental Chagas disease. For that, we assessed the earlier (acute phase) and also the later (chronic phase) use of Epo in infected C57BL/6 mice. Blood cell count, biochemical parameters, parasitic load, and echocardiography data were evaluated. In addition, histopathological analysis was carried out. Our data showed that Epo had no trypanocide effect nor did it modify the production of anti-T. cruzi antibodies. Epo-treated groups exhibited parasitic burden much lower in the heart compared to blood. No pattern of hematological changes was observed combining infection with treatment with Epo. Chronic Epo administration reduced CK-MB serum activity from d0 to d180, irrespectively of T. cruzi infection. Likewise, echocardiography and histological results indicate that Epo treatment is more effective in the chronic phase of experimental Chagas disease. Since treatment is one of the greatest challenges of Chagas disease, alternative therapies should be investigated, including Epo combined with benznidazole.


Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Eritropoetina , Tripanossomicidas , Trypanosoma cruzi , Animais , Cardiomiopatia Chagásica/tratamento farmacológico , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Eritropoetina/farmacologia , Eritropoetina/uso terapêutico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
7.
ChemMedChem ; 17(15): e202200196, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35678042

RESUMO

Chagas disease, a neglected tropical disease, is endemic in 21 Latin American countries and particularly prevalent in Brazil. Chagas disease has drawn more attention in recent years due to its expansion into non-endemic areas. The aim of this work was to computationally identify and experimentally validate the natural products from an Annonaceae family as antichagasic agents. Through the ligand-based virtual screening, we identified 57 molecules with potential activity against the epimastigote form of T. cruzi. Then, 16 molecules were analyzed in the in vitro study, of which, six molecules displayed previously unknown antiepimastigote activity. We also evaluated these six molecules for trypanocidal activity. We observed that all six molecules have potential activity against the amastigote form, but no molecules were active against the trypomastigote form. 13-Epicupressic acid seems to be the most promising, as it was predicted as an active compound in the in silico study against the amastigote form of T. cruzi, in addition to having in vitro activity against the epimastigote form.


Assuntos
Annonaceae , Produtos Biológicos , Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
8.
Vet Parasitol ; 306: 109723, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35643575

RESUMO

Trypanosoma (T.) vivax is one of the animal trypanosomes species causing calf mortality and economic losses in Togo. Despite its importance as the most widely distributed trypanosome species, T. vivax has received little attention because it is difficult to cultivate most field isolates in rodents. No molecular diagnostic tools for the identification of drug-resistant in T. vivax are currently available. Herein, four field isolates of T. vivax from Togo were cryopreserved and assessed for susceptibility to diminazene aceturate (DA) and isometamidium chloride (ISM) in goats. For field isolate preparation, 1 ml of blood from an infected goat was diluted in 111 µl of phosphate-buffered-saline and stored in liquid nitrogen. The in vivo experiment drug test was performed using twenty Sahelian goats with six-month of age and weighing 14.5 ± 1.6 kg. These experimental goats were purchased from a tsetse free-area Dori, a Sahelian region of Burkina Faso. The cryopreserved T. vivax isolates with unknowns, DA, and ISM sensitivity was inoculated to five goats and one goat was used as control. Each animal was inoculated by intravenously route 1 × 105 trypanosomes from the donor goat. Relapses were earlier in the first phase of treatment (14.85 ± 1.08 days) compared with the second phase (20 ± 3.39 days). The overall mean PCV of the control group decreased from 32% to 17% at day-60 (P-value < 0.001). Three isolates were phenotypically resistant to 0.5 mg per kg body weight (BW) ISM and one for 3.5 mg per kg BW of DA. There were no relapses with the 7 mg per kg BW dose DA. This study shows the resistance of T. vivax to two main trypanocidal drugs in different villages of Mango. The results suggest the extension of surveillance strategies to remote villages in Togo and will guide the veterinarian or herder in choosing a mass treatment strategy. Further studies will be needed to better understand the molecular basis of the observed resistance.


Assuntos
Doenças das Cabras , Tripanossomicidas , Trypanosoma , Tripanossomíase Africana , Animais , Doenças das Cabras/tratamento farmacológico , Cabras , Togo/epidemiologia , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma vivax , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/veterinária
9.
Molecules ; 27(12)2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35744891

RESUMO

Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (SPR10-SPR19) as potential anti-HAT agents. The new molecules show Ki values in the low-micro/sub-micromolar range against rhodesain, coupled with k2nd values between 1314 and 6950 M-1 min-1. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor SPR34 highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , África do Norte , Animais , Inibidores de Cisteína Proteinase/química , Humanos , Mamíferos , Tripanossomicidas/química , Tripanossomíase Africana/tratamento farmacológico
10.
Int J Mol Sci ; 23(11)2022 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-35682786

RESUMO

Sleeping sickness or African trypanosomiasis is a serious health concern with an added socio-economic impact in sub-Saharan Africa due to direct infection in both humans and their domestic livestock. There is no vaccine available against African trypanosomes and its treatment relies only on chemotherapy. Although the current drugs are effective, most of them are far from the modern concept of a drug in terms of toxicity, specificity and therapeutic regime. In a search for new molecules with trypanocidal activity, a high throughput screening of 2000 microbial extracts was performed. Fractionation of one of these extracts, belonging to a culture of the fungus Amesia sp., yielded a new member of the curvicollide family that has been designated as curvicollide D. The new compound showed an inhibitory concentration 50 (IC50) 16-fold lower in Trypanosoma brucei than in human cells. Moreover, it induced cell cycle arrest and disruption of the nucleolar structure. Finally, we showed that curvicollide D binds to DNA and inhibits transcription in African trypanosomes, resulting in cell death. These results constitute the first report on the activity and mode of action of a member of the curvicollide family in T. brucei.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Fungos , Humanos , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Tripanossomíase Africana/tratamento farmacológico
11.
Future Med Chem ; 14(11): 795-808, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35543430

RESUMO

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC50 = 0.536 µm) and trypanocidal activity (IC50 = 0.990 µm). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q2 = 0.786; r2 = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.


Assuntos
Doença de Chagas , Chalcona , Chalconas , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Chalcona/farmacologia , Chalconas/farmacologia , Cisteína Endopeptidases , Humanos , Ligantes , Simulação de Acoplamento Molecular , Proteínas de Protozoários , Relação Estrutura-Atividade , Tiofenos/farmacologia , Tripanossomicidas/farmacologia
12.
Eur J Med Chem ; 238: 114460, 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35597010

RESUMO

Parasitic cysteine proteases such as rhodesain (TbCatL) from Trypanosoma brucei rhodesiense are relevant targets for developing new potential drugs against parasitic diseases (e. g. Human African Trypanosomiasis). Designing selective inhibitors for parasitic cathepsins can be challenging as they share high structural similarities with human cathepsins. In this paper, we describe the development of novel peptidomimetic rhodesain inhibitors by applying a structure-based de novo design approach and molecular docking protocols. The inhibitors with a new scaffold in P2 and P3 position display high selectivity towards trypanosomal rhodesain over human cathepsins L and B and high antitrypanosomal activity. Vinylsulfonate 2a has emerged as a potent rhodesain inhibitor (k2nd = 883 • 103 M-1 s-1) with single-digit nanomolar binding affinity (Ki = 9 nM) and more than 150-fold selectivity towards human cathepsins and it thus constitutes an interesting starting compound for the further development of selective drugs against Human African Trypanosomiasis.


Assuntos
Peptidomiméticos , Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Catepsinas , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/química , Humanos , Simulação de Acoplamento Molecular , Peptidomiméticos/farmacologia , Peptidomiméticos/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/tratamento farmacológico
13.
Exp Parasitol ; 238: 108266, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35490799

RESUMO

Treatment for Chagas disease has limited efficacy in the chronic phase. We evaluated benznidazole (BZ) and itraconazole (ITZ) individually and in association in dogs 16 months after infection with a BZ-resistant Trypanosoma cruzi strain. Four study groups (20 animals) were evaluated and treated for 60 days with BZ, ITZ, or BZ + ITZ, and maintained in parallel to control group infected and not treated (INT). All dogs were evaluated in the first, sixth, 12th, 18th and 24th months of study. Polymerase chain reaction (PCR) was negative in 2 of 3 animals in the BZ + ITZ group, 2 of 5 in the BZ group, and 4 of 5 in the ITZ group. Hemoculture performed in the 24th month was negative in all groups. Enzyme-linked immunoassay remained reactive in all treated animals. Echocardiography differentiated treated animals from control animals. Quantitative PCR analysis of cardiac tissue was negative in the BZ + ITZ and BZ groups, positive in 2 of 5 dogs in the ITZ group and in 2 of 3 dogs in the control group, but negative in colon tissue in all groups. Inflammation was significantly reduced in the right atrium and left ventricle of dogs treated with BZ + ITZ and BZ compared with those receiving ITZ alone. Fibrosis was absent in most dogs treated with BZ + ITZ, mild in those treated with BZ or ITZ alone, and intense in the control group. Parasitological and histopathological evaluations showed that BZ + ITZ treatment improved or stabilized the clinical condition of the dogs.


Assuntos
Doença de Chagas , Nitroimidazóis , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Doença de Chagas/patologia , Doença de Chagas/veterinária , Cães , Itraconazol/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico
14.
Parasitol Res ; 121(7): 2141-2156, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35610523

RESUMO

Chagas disease (CD) is a neglected disease, prevalent and endemic in Latin America, but also present in Europe and North America. The main treatment used for this disease is benznidazole, but its efficacy is variable in the chronic phase and presents high toxicity. So, there is a need for the development of new therapeutic agents. The five-membered heterocyclic 1,2,4-oxadiazole ring has received attention for its unique properties and a broad spectrum of biological activities and is therefore a potential candidate for the development of new drugs. Thus, the aim of this study was to evaluate the activity of the N-cyclohexyl-3-(3-methylphenyl)-1,2,4-oxadiazol-5-amine (2) on the evolutionary forms of Trypanosoma cruzi strain Y, as well as its mechanisms of action and in silico theoretical approach. The results by computational method showed an interaction of the 1,2,4-oxadiazole (2) with TcGAPDH, cruzain, and trypanothione reductase, showing good charge distribution and affinity in those three targets. Furthermore, cytotoxicity in LLC-MK2 cells was performed by the MTT method. In the assays with different parasite forms, the tested compound showed similar time-dependent concentration effect. The evaluation of the antiamastigote effect between the two concentrations tested showed a reduction in the number of infected cells and also in the number of amastigotes per infected cell. By flow cytometry, the compound (2) displayed alterations suggestive of necrotic events. Finally, in scanning electron microscopy structural alterations were present, characteristic of necrosisin the epimastigote forms. Overall, the 1,2,4-oxadiazole derivative (2) here evaluated opens perspectives to the development of new antichagasic agents.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Linhagem Celular , Doença de Chagas/tratamento farmacológico , Humanos , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
16.
Mem Inst Oswaldo Cruz ; 117: e200501, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35613156

RESUMO

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. There is an urgent need for safe, effective, and accessible new treatments since the currently approved drugs have serious limitations. Drug development for Chagas disease has historically been hampered by the complexity of the disease, critical knowledge gaps, and lack of coordinated R&D efforts. This review covers some of the translational challenges associated with the progression of new chemical entities from preclinical to clinical phases of development, and discusses how recent technological advances might allow the research community to answer key questions relevant to the disease and to overcome hurdles in R&D for Chagas disease.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , Doenças Negligenciadas/tratamento farmacológico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
17.
Phytomedicine ; 101: 154126, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35489322

RESUMO

BACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi, affects over six million people worldwide, mainly in Latin American countries. Currently available drugs have variable efficacy in the chronic phase and significant side effects, so there is an urgent need for safer chemotherapeutic treatments. Natural products provide privileged structures that could serve as templates for the synthesis of new drugs. Among them, Amaryllidaceae plants have proved to be a potential natural source of therapeutical agents due to their rich diversity in alkaloids. PURPOSE: To identify alkaloids with anti-T. cruzi activity from Habranthus brachyandrus (Baker) Sealy (Amaryllidaceae, subfamily Amaryllidoideae) collected in Argentina. METHODS: An H. brachyandrus alkaloid extract was tested against T. cruzi, and its cytotoxicity profile was evaluated against two mammalian cell lines to ascertain its selectivity against the parasite and potential liver toxicity. It was also assessed by a stage-specific anti-amastigote assay and analysed by GC/MS to determine its alkaloid profile. The isolated alkaloids were also tested using the aforementioned assays. RESULTS: The extract showed high and specific activity against T. cruzi. The alkaloids lycoramine, galanthindole, 8-O-demethylmaritidine, 8-O-demethylhomolycorine, nerinine, trisphaeridine, deoxytazettine, and tazettamide were identified by means of GC-MS. In addition, hippeastidine (also named aulicine), tazzetine, ismine, and 3-epimacronine were isolated. The alkaloid ismine was specifically active against the parasite and had low toxicity against HepG2 cells, but did not show anti-amastigote activity. CONCLUSION: The extract had specific anti-T. cruzi activity and the isolated alkaloid ismine was partially responsible of it. These results encourage further exploration of H. brachyandrus alkaloids in search of novel starting points for Chagas disease drug development.


Assuntos
Alcaloides , Alcaloides de Amaryllidaceae , Amaryllidaceae , Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Alcaloides/uso terapêutico , Amaryllidaceae/química , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacologia , Animais , Argentina , Doença de Chagas/tratamento farmacológico , Humanos , Mamíferos , Extratos Vegetais/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
18.
Bioorg Med Chem ; 61: 116740, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35396128

RESUMO

Human African trypanosomiasis is caused by a protozoan parasite Trypanosoma brucei majorly infecting people living in sub-Saharan Africa. Current limited available treatments suffer from drug resistance, severe adverse effects, low efficacy, and costly administrative procedures in African countries with limited medical resources. Therefore, there is always a perpetual demand for advanced drug development and invention of new strategies to combat the disease. Previous work in our lab generated a library of sulfonamide analogs as selective tubulin inhibitors, based on the structural difference between mammalian and trypanosome tubulin proteins. Further lead derivatization was performed in the current study and generated 25 potential drug candidates to improve the drug efficacy and uptake by selectively targeting the parasite's P2 membrane transporter protein with imidamide moiety. One of the newly synthesized analogs, compound 25 with a di-imidamide moiety, has shown greater potency with an IC50 of 1 nM to selectively inhibit the growth of trypanosome cells without affecting the viability of mammalian cells. Western blot analyses reveal that the compound suppressed tubulin polymerization in T. brucei cells. A detailed structure-activity relationship (SAR) was summarized that will be used to guide future lead optimization.


Assuntos
Tripanossomicidas , Trypanosoma brucei brucei , Tripanossomíase Africana , Animais , Humanos , Mamíferos/metabolismo , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologia
19.
Eur J Med Chem ; 236: 114328, 2022 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-35385806

RESUMO

In this paper, we developed a new series of dipeptide nitriles that were demonstrated to be reversible rhodesain inhibitors at nanomolar level, with EC50 values against cultured T. b. brucei in the micromolar range. We also proved that our dipeptide nitriles directly bind to the active site of rhodesain acting as competitive inhibitors. Within the most interesting compounds, the dipeptide nitrile 2b showed the highest binding affinity towards rhodesain (Ki = 16 nM) coupled with a good antiparasitic activity (EC50 = 14.1 µM). Moreover, for the dipeptide nitrile 3e, which showed a Ki = 122 nM towards the trypanosomal protease, we obtained the highest antiparasitic activity (EC50 = 8.8 µM). Thus, given the obtained results both compounds could certainly represent new lead compounds for the discovery of new drugs to treat Human African Trypanosomiasis.


Assuntos
Inibidores de Cisteína Proteinase , Dipeptídeos , Nitrilas , Tripanossomicidas , Trypanosoma brucei rhodesiense , Cisteína Endopeptidases , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Nitrilas/química , Nitrilas/farmacologia , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos
20.
Chem Biol Interact ; 361: 109920, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35461787

RESUMO

Chagas disease is a disease that is emerging in North America and Europe countries. Benznidazole is the main drug available, but it has high toxicity and low efficacy in the chronic phase. In this way, researching new antichagasic agents is necessary. Thus, the aim of this study is to evaluate the effect of novel chalcones and the influence of chlorine substitutions on Trypanosoma cruzi and host cells. Unsubstituted (1), 4-chlorine substituted (2) and 2,4-chlorine substituted (3) chalcones were synthesized by Claisen-Schmidt condensation, characterized, and electrical distribution was assessed by Density Fuctional Theory (DFT). The host cells toxicity (LLC-MK2) was performed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) reduction assay. The effect on epimastigote (24, 48 and 72h), trypomastigote (24h) and amastigotes (24 h) was evaluated. Flow cytometry assays were performed with 7-Aminoactinomycin D (7-AAD) and Annexin-PE, Dichlorofluorescein diaceteate (DCFH-DA) and Rhodamine123 (Rho123). Finally, molecular docking predicted interactions between chalcones and cruzain (TcCr) and trypanothione reductase (TcTR). The toxicity on host cells was reduced almost twenty times on chlorine substituted molecules. On epimastigote and trypomastigote forms, all substances presented similar effects. After treatment with molecule 3, it was observed a decrease in infected cells and intracellular amastigotes. Their effect is related to necrotic events, increase of cytoplasmic Reactive Oxygen Species (ROS) and mitochondrial dysfunction. Also, this effect might be associated with involvement of TcCr and TcTR enzymes. Therefore, the results showed that chlorine substitution on chalcones reduces the host cell's toxicity without compromising the effect on Trypanosoma cruzi Y strain forms, and it occurs over membrane damage, oxidative stress and possible interactions with TcCr and TcTR.


Assuntos
Doença de Chagas , Chalcona , Chalconas , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Chalcona/farmacologia , Chalconas/farmacologia , Chalconas/uso terapêutico , Cloretos/farmacologia , Cloro , Humanos , Simulação de Acoplamento Molecular , Tripanossomicidas/farmacologia
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