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1.
J Enzyme Inhib Med Chem ; 35(1): 21-30, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619095

RESUMO

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Doença de Chagas/tratamento farmacológico , Ciclamatos/farmacologia , Tripanossomicidas/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Doença de Chagas/metabolismo , Ciclamatos/síntese química , Ciclamatos/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia
2.
BMC Infect Dis ; 19(1): 956, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706289

RESUMO

BACKGROUND: Current available treatments (benznidazole and nifurtimox) for Chagas disease (CD) show limited efficacy in chronic phase and frequent undesirable effects. Ergosterol synthesis inhibitors (ESI) had been considered as promising drugs for CD treatment and despite its recent poor results in several clinical trials, different strategies have been proposed to optimize its role in this infection. CASE PRESENTATION: We present a case of chronic Chagas disease in patient diagnosed with HIV who received treatment for histoplasmosis with itraconazol during twelve months. Even though T. cruzi rt-PCR was persistently negative during treatment, when itraconazol was stopped she presented with a positive blood rt-PCR. CONCLUSION: Several studies using different ESI had been published for CD treatment. Either in vitro or in vivo assays demonstrated activity against T. cruzi of the different triazole derivatives so different clinical trials had been carried out to evaluate its efficacy and safety. Despite contradictory evidence in the animal model, longer treatments along with other treatment strategies previously proposed suggests that ESI failure rates in positive peripheral blood rt-PCR are higher than that obtained with the current treatments of choice.


Assuntos
Doença de Chagas/tratamento farmacológico , Itraconazol/uso terapêutico , Tripanossomicidas/uso terapêutico , Adulto , Animais , Contagem de Linfócito CD4 , Doença de Chagas/complicações , Doença Crônica , Feminino , Infecções por HIV/complicações , Infecções por HIV/diagnóstico , Humanos , Itraconazol/farmacologia , Tomografia Computadorizada por Raios X , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos
3.
Chem Biodivers ; 16(11): e1900359, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31544347

RESUMO

The objective of this study was to evaluate the chemical composition, and the trypanocidal and antibacterial activities of the essential oils from four species of Annonaceae: Bocageopsis multiflora (Mart.) R.E.Fr., Duguetia quitarensis Benth., Fusaea longifolia (Aubl.) Saff., and Guatteria punctata (Aubl.) R.A.Howard. The chemical composition of the essential oils from the aerial parts yielded 23, 20, 21 and 23 constituents, respectively, which were identified by GC/MS. The trypanocidal activity was evaluated against the amastigote and trypomastigote forms of T. cruzi. The antibacterial activity was evaluated by the microdilution method against enterohemorrhagic Escherichia coli, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus pyogenes, and methicillin-resistant Staphylococcus aureus. The results of trypanocidal activity showed that the essential oils of the four species were active at the tested concentrations, with G. punctata essential oil being the most active, with IC50 =0.029 µg/mL, and selectivity index (SI)=32, being 34 times more active than the reference drug benznidazole. All EOs showed strong antibacterial activity (minimum inhibitory concentrations of 4.68-37.5 µg/mL) against strains of S. mutans.


Assuntos
Annonaceae/química , Antibacterianos/farmacologia , Óleos Voláteis/farmacologia , Tripanossomicidas/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Testes de Sensibilidade Parasitária , Pseudomonas aeruginosa/efeitos dos fármacos , Especificidade da Espécie , Streptococcus mutans/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Trypanosoma cruzi/efeitos dos fármacos
4.
PLoS Negl Trop Dis ; 13(9): e0007226, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31536489

RESUMO

Chagas disease, caused by Trypanosoma cruzi, is a neglected tropical disease that affects 5-6 million people in endemic areas of the Americas. Presently, chemotherapy relies on two compounds that were proposed as trypanocidal drugs four decades ago: nifurtimox and benznidazole. Both drugs are able to eliminate parasitemia and to avoid seroconversion in infected people when used in the acute phase; however, their use in the chronic phase (the time when the majority of cases are diagnosed) is limited due to their serious side effects. Memantine is a glutamate receptor antagonist in the central nervous system of mammals that has been used for the treatment of Alzheimer's disease. Our group previously reported memantine as a trypanocidal drug that is able to induce apoptosis-like death in T. cruzi. In the present work, we further investigated the effects of memantine on the infection of RAW 264.7 macrophages and in vivo (in BALB/c mice). Here, we showed that memantine is able to diminish NO and Ca2+ entry in both LPS-activated and non-activated cells. These results, together with the fact that memantine was also able to reduce the infection of macrophages, led us to propose that this drug is able to activate a pro-oxidant non-NO-dependent cell defense mechanism. Finally, infected mice that were treated with memantine had diminished parasitemia, cardiac parasitic load, and inflammatory infiltrates. In addition, the treated mice had an increased survival rate. Taken together, these results indicate memantine to be a candidate drug for the treatment of Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Memantina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Cálcio/metabolismo , Doença de Chagas/parasitologia , Feminino , Coração/parasitologia , Lipopolissacarídeos/farmacologia , Macrófagos/parasitologia , Memantina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Óxidos de Nitrogênio/metabolismo , Carga Parasitária , Parasitemia , Células RAW 264.7 , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tripanossomicidas/administração & dosagem
5.
Molecules ; 24(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487860

RESUMO

Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores -10.27 kcal/mol to -5.29 kcal/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score -10.27 kcal/mol) inhibited 32.9% the enzyme activity (100 µM) and showed the highest leishmanicidal activity (IC50 = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 µM) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/enzimologia , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Sequência de Aminoácidos , Sítios de Ligação , Relação Dose-Resposta a Droga , Ligações de Hidrogênio , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Farmacocinética , Proteínas Recombinantes/química , Relação Estrutura-Atividade
6.
Exp Parasitol ; 206: 107730, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494215

RESUMO

Phospholipids are the main component of membranes and are responsible for cell integrity. Alkylphospholipid analogues (APs) were first designed as antitumoral agents and were later tested against different cell types. Trypanosoma cruzi, the Chagas disease etiological agent, is sensitive to APs (edelfosine, miltefosine and ilmofosine) in vitro. We investigated the effect of synthetic ring substituted AP against epimastigotes, amastigotes and trypomastigotes. TCAN26, could inhibit the in vitro growth of epimastigotes and amastigotes with the 50% inhibitory concentrations (IC50) in the nanomolar range. Trypomastigotes lysis was also induced with 24-h treatment and a LC50 of 2.3 µM. Ultrastructural analysis by electron microscopy demonstrated that TCAN26 mainly affected the parasite's membranes leading to mitochondrial and Golgi cisternae swelling, membrane blebs, and autophagic figures in the different parasite developmental stages. While the Golgi of the parasites was significantly affected, the Golgi complex of the host cells remained normal suggesting a specific mechanism of action. In summary, our results suggest that TCAN 26 is a potent and selective inhibitor of T. cruzi growth probably due to disturbances of phospholipid biosynthesis.


Assuntos
Adamantano/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Adamantano/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Autofagia/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Complexo de Golgi/efeitos dos fármacos , Concentração Inibidora 50 , Dose Letal Mediana , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitocôndrias/efeitos dos fármacos , Fosforilcolina/química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
7.
Expert Opin Pharmacother ; 20(15): 1797-1807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456439

RESUMO

Introduction: As benznidazole is the first-line treatment for patients with Chagas disease, rational chemotherapy strategies are required based on the critical analysis of the evidence on the relevance and applicability of this drug at different disease stages. Areas covered: The authors discuss the current understanding of benznidazole-based chemotherapy for Chagas disease, focusing specifically on epidemiology, pharmacokinetics, mechanism of action, clinical recommendations, cure criteria, and therapeutic efficacy in different phases of the disease. Expert opinion: Benznidazole shows high bioavailability after oral administration. Benznidazole at 5-8 mg/kg/day and 5-10 mg/kg/day for 30-60 days are consistent clinical recommendations for children and adults, respectively. A high correlation between negative parasitological, serological, and polymerase chain reaction (PCR) assays in long-term post-therapeutic follow-up has been consistently used to evaluate therapeutic efficacy. These methods support the evidence that the success of benznidazole-based chemotherapy is closely correlated with the phase of infection in which the treatment is administered. The greater therapeutic efficacy is obtained in acute infections, gradually worsening as the infection becomes chronic. When therapeutic failure is confirmed by any diagnostic assay, benznidazole treatment does not always ensure better long-term prognosis, and Chagas cardiomyopathy may develop as well as in untreated patients.


Assuntos
Doença de Chagas/tratamento farmacológico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Adulto , Criança , Feminino , Humanos , Nitroimidazóis/farmacologia , Prognóstico , Tripanossomicidas/farmacologia
8.
Mem Inst Oswaldo Cruz ; 114: e190111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31433006

RESUMO

BACKGROUND: In addition to the limited therapeutic arsenal and the side effects of antileishmanial agents, drug resistance hinders disease control. In Brazil, Leishmania braziliensis causes atypical (AT) tegumentary leishmaniasis lesions, frequently refractory to treatment. OBJECTIVES: The main goal of this study was to characterise antimony (Sb)-resistant (SbR) L. braziliensis strains obtained from patients living in Xakriabá indigenous community, Minas Gerais, Brazil. METHODS: The aquaglyceroporin 1-encoding gene (AQP1) from L. braziliensis clinical isolates was sequenced, and its function was evaluated by hypo-osmotic shock. mRNA levels of genes associated with Sb resistance were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Atomic absorption was used to measure Sb uptake. FINDINGS: Although clinical isolates presented delayed recovery time in hypo-osmotic shock, AQP1 function was maintained. Isolate 340 accumulated less Sb than all other isolates, supporting the 65-fold downregulation of AQP1 mRNA levels. Both 330 and 340 isolates upregulated antimony resistance marker (ARM) 56/ARM58 and multidrug resistant protein A (MRPA); however, only ARM58 upregulation was an exclusive feature of SbR field isolates. CA7AE seemed to increase drug uptake in L. braziliensis and represented a tool to study the role of glycoconjugates in Sb transport. MAIN CONCLUSIONS: There is a clear correlation between ARM56/58 upregulation and Sb resistance in AT-harbouring patients, suggesting the use of these markers as potential indicators to help the treatment choice and outcome, preventing therapeutic failure.


Assuntos
Antimônio/farmacologia , Resistência a Medicamentos/genética , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose Cutânea/parasitologia , Proteínas de Protozoários/genética , Tripanossomicidas/farmacologia , Aquagliceroporinas/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Leishmania braziliensis/genética , Testes de Sensibilidade Parasitária , Proteínas de Protozoários/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
9.
Eur J Med Chem ; 182: 111610, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434040

RESUMO

Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Imidazolinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Imidazolinas/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Pirazóis/química , Pirimidinas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Células Vero
10.
Acta Trop ; 199: 105120, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31376368

RESUMO

Chagas disease has become a global health problem due to migration of infected people out of Latin America to non-endemic countries. For more than 40 years, only the nitroimidazole compounds Benznidazole and Nifurtimox, have been used for specific treatment of Trypanosoma cruzi infection with disappointing results, specially due to the long duration of treatment and adverse events in the chronic phase. In the last years, ergosterol inhibitors have been also proposed for specific treatment. Different randomized clinical trials were performed for evaluating their treatment efficacy and safety. One of the greatest concerns in clinical trials is to provide an early surrogate biomarker of response to trypanocidal chemotherapy. Serological response is slow and the classical parasitological tests have poor sensitivity and are time-consuming. Nowadays, PCR is the most helpful tool for assessing treatment response in a short period of time. Different protocols of PCR have been developed, being quantitative real time PCR based on amplification of repetitive satellite or minicircle DNA sequences plus an internal amplification standard, the mostly employed strategies in clinical trials. Standardized protocols and the use of an external quality assessment ensure adequate technical procedures and reliable data. Clinical trials have shown a significant reduction in parasite loads, reaching undetectable DNA levels in bloodstream after specific treatment, however events of treatment failure have also been reported. Treatment failure could be due to inadequate penetrance of the drugs into the affected tissues, to the presence of primary or secondary drug resistance of the infecting strains as well as to the existence of dormant parasite variants reluctant to drug action. The early diagnosis of drug resistance would improve clinical management of Chagas disease patients, allowing dictating alternative therapies with a combination of existing drugs or new anti-T. cruzi agents. The aim of this review was to describe the usefulness of detecting T.cruzi DNA by means of real time PCR assays, as surrogate biomarker in clinical trials for evaluating new drugs for CD or new regimens of available drugs and the possibility to detect treatment failure.


Assuntos
Doença de Chagas/terapia , Ácidos Nucleicos/análise , Reação em Cadeia da Polimerase em Tempo Real , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Biomarcadores , Doença de Chagas/parasitologia , Doença Crônica , Resistência a Medicamentos/genética , Humanos , Nifurtimox/farmacologia , Nifurtimox/uso terapêutico , Nitroimidazóis/farmacologia , Nitroimidazóis/uso terapêutico , Ácidos Nucleicos/sangue , Carga Parasitária , Falha de Tratamento , Resultado do Tratamento , Tripanossomicidas/farmacologia , Trypanosoma cruzi/genética
12.
J Appl Microbiol ; 127(5): 1373-1380, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31339616

RESUMO

AIMS: Violacein (VIO), a bacterial pigment produced by Chromobacterium violaceum, was examined to evaluate the antichagasic activity and its action mechanism against Trypanosoma cruzi Y strain. METHODS AND RESULTS: Violacein was tested against the epimastigote, trypomastigote and amastigote forms of T. cruzi Y strain (benznidazole-resistant strain). VIO inhibited all T. cruzi developmental forms, including amastigotes, which is implicated in the burden of infection in the chronic phase of Chagas disease (CD). VIO induced cell death in T. cruzi through apoptosis, as determined by flow cytometry analyses with specific molecular probes and morphological alterations, such as involvement of reactive oxygen species and changes in mitochondrial membrane potential and cell shrinkage. CONCLUSION: The results suggest antichagasic activity of VIO against T. cruzi Y strain with apoptotic involvement. SIGNIFICANCE AND IMPACT OF THE STUDY: The treatment of CD has limited efficacy and side effects that restrict patient tolerability and compliance. The VIO molecule could be used as a model for therapeutic alternatives for this disease.


Assuntos
Chromobacterium/química , Indóis/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular , Resistência a Medicamentos , Humanos , Indóis/isolamento & purificação , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nitroimidazóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Trypanosoma cruzi/crescimento & desenvolvimento
13.
Eur J Med Chem ; 180: 191-203, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306906

RESUMO

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16-26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC50 of 2.6 µM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.


Assuntos
Desenho de Drogas , Tiazóis/farmacologia , Tiossemicarbazonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
14.
Eur J Med Chem ; 180: 213-223, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306908

RESUMO

Reactions of Ni(II) and Pd(II) precursors with S-benzyl-N-(ferrocenyl)methylenedithiocarbazate (HFedtc) led to the formation of heterobimetallic complexes of the type [MII(Fedtc)2] (M = Ni and Pd). The characterization of the compounds involved the determination of melting point, FTIR, UV-Vis, 1H NMR, elemental analysis and electrochemical experiments. Furthermore, the crystalline structures of HFedtc and [NiII(Fedtc)2] were determined by single crystal X-ray diffraction. The compounds were evaluated against the intracellular form of Trypanosoma cruzi (Tulahuen Lac-Z strain) and the cytotoxicity assays were assessed using LLC-MK2 cells. The results showed that the coordination of HFedtc to Ni(II) or Pd(II) decreases the in vitro trypanocidal activity while the cytotoxicity against LLC-MK2 cells does not change significantly. [PdII(Fedtc)2] showed the greater potential between the two complexes studied, showing an SI value of 8.9. However, this value is not better than that of the free ligand with an SI of 40, a similar value to that of the standard drug benznidazole (SI = 48). Additionally, molecular docking simulations were performed with Trypanosoma cruzi Old Yellow Enzyme (TcOYE), which predicted that HFedtc binds to the protein, almost parallel to the flavin mononucleotide (FMN) prosthetic group, while the [NiII(Fedtc)2] complex was docked into the enzyme binding site in a significantly different manner. In order to confirm the hypothetical interaction, in vitro experiments of fluorescence quenching and enzymatic activity were performed which indicated that, although HFedtc was not processed by the enzyme, it was able to act as a competitive inhibitor, blocking the hydride transfer from the FMN prosthetic group of the enzyme to the menadione substrate.


Assuntos
Compostos de Benzil/farmacologia , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Metalocenos/farmacologia , NADPH Desidrogenase/antagonistas & inibidores , Níquel/farmacologia , Paládio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Hidrazinas/química , Macaca mulatta , Metalocenos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , NADPH Desidrogenase/química , NADPH Desidrogenase/metabolismo , Níquel/química , Níquel/metabolismo , Paládio/química , Paládio/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/metabolismo , Trypanosoma cruzi/metabolismo
15.
Inorg Chem ; 58(15): 10129-10138, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31310108

RESUMO

A series of 16 "3 + 2" mixed-ligand complexes of the general composition [ReO(L1)(L2)] (H2L1a-H2L1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents; HL2a-HL2d = bidentate N,N-diethyl-N'-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the 13C NMR chemical shifts of the N-C═N carbon atoms of the {L1}2- and the C═O carbon atoms of the {L2}- ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two Trypanosoma cruzi strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu4)[TcOCl4] and two representatives of the fluorinated ligands (H2L1b, 4-F-substituted, and H2L1c, 4-CF3-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.


Assuntos
Complexos de Coordenação/farmacologia , Halogenação , Rênio/farmacologia , Tiossemicarbazonas/farmacologia , Tioureia/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cristalografia por Raios X , Haplorrinos , Ligantes , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Rênio/química , Tiossemicarbazonas/química , Tioureia/química , Tripanossomicidas/síntese química , Tripanossomicidas/química
16.
Exp Parasitol ; 204: 107724, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279930

RESUMO

Only two drugs are currently available for the treatment of Chagas disease and their effectiveness are unsatisfactory. Photorhabdus luminescens and Xenorhabdus nematophila, two enteric bacteria highly pathogenic to a broad range of insects, have been studied as potential source for bioactive metabolites against protozoa causing neglected tropical diseases. Therefore, we tested the in vitro anti-Trypanosoma cruzi activity of secreted metabolites from these bacteria. The conditioned medium of X. nematophila and P. luminescens showed significant parasiticidal activity in a concentration-dependent manner (IC50XN = 0.34 mg/mL, IC50PL = 1.0 mg/mL). The parasiticidal compound was identified as a small molecule stable to heating and pH changes ranging from 2 to 12. Moreover, anti-Trypanosoma molecules secreted by both bacteria stimulate the trypanocidal activity of macrophages by a mechanism independent of nitric oxide. Summarizing, our studies reveal that P. luminescens and X. nematophila are potential sources of putative novel drugs against Chagas disease.


Assuntos
Proteínas de Bactérias/farmacologia , Photorhabdus/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Xenorhabdus/química , Análise de Variância , Animais , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/uso terapêutico , Bioensaio , Doença de Chagas/tratamento farmacológico , Meios de Cultivo Condicionados , Endopeptidase K/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Temperatura Ambiente , Tripanossomicidas/efeitos adversos , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/crescimento & desenvolvimento
17.
Eur J Med Chem ; 179: 765-778, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284086

RESUMO

Chagas disease, Human African Trypanosomiasis, and schistosomiasis are neglected parasitic diseases for which new treatments are urgently needed. To identify new chemical leads, we screened the 400 compounds of the Open Access Malaria Box against the cysteine proteases, cruzain (Trypanosoma cruzi), rhodesain (Trypanosoma brucei) and SmCB1 (Schistosoma mansoni), which are therapeutic targets for these diseases. Whereas just three hits were observed for SmCB1, 70 compounds inhibited cruzain or rhodesain by at least 50% at 5 µM. Among those, 15 commercially available compounds were selected for confirmatory assays, given their potency, time-dependent inhibition profile and reported activity against parasites. Additional assays led to the confirmation of four novel classes of cruzain and rhodesain inhibitors, with potency in the low-to mid-micromolar range against enzymes and T. cruzi. Assays against mammalian cathepsins S and B revealed inhibitor selectivity for parasitic proteases. For the two competitive inhibitors identified (compounds 7 and 12), their binding mode was predicted by docking, providing a basis for structure-based optimization efforts. Compound 12 also acted directly against the trypomastigote and the intracellular amastigote forms of T. cruzi at 3 µM. Therefore, through a combination of experimental and computational approaches, we report promising hits for optimization in the development of new trypanocidal drugs.


Assuntos
Cisteína Proteases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Descoberta de Drogas , Malária/tratamento farmacológico , Schistosoma mansoni/metabolismo , Tripanossomicidas/farmacologia , Animais , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Malária/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Schistosoma mansoni/efeitos dos fármacos , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/metabolismo
18.
Curr Med Chem ; 26(36): 6672-6686, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284853

RESUMO

Chagas disease is a neglected tropical illness caused by the protozoan parasite Trypanosoma cruzi. The disease is endemic in Latin America with about 6 million people infected and many more being at risk. Only two drugs are available for treatment, Nifurtimox and Benznidazole, but they have a number of side effects and are not effective in all cases. This makes urgently necessary the development of new drugs, more efficient, less toxic and affordable to the poor people, who are most of the infected population. In this review we will summarize the current strategies used for drug discovery considering drug repositioning, phenotyping screenings and target-based approaches. In addition, we will describe in detail the considerations for setting up robust enzymatic assays aimed at identifying and validating small molecule inhibitors in high throughput screenings.


Assuntos
Inibidores de Cisteína Proteinase/farmacologia , Descoberta de Drogas/métodos , Tripanossomicidas/farmacologia , Doença de Chagas/tratamento farmacológico , Cisteína Endopeptidases , Reposicionamento de Medicamentos , Ensaios Enzimáticos/métodos , Ensaios de Triagem em Larga Escala/métodos , Proteínas de Protozoários/antagonistas & inibidores , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia
19.
Fitoterapia ; 137: 104251, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271783

RESUMO

The MeOH extract from leaves of Saururus cernuus L. (Saururaceae) displayed in vitro activity against trypomastigote forms of T. cruzi (100% of parasite death at 200 µg/mL), suggesting the presence of bioactive compounds. Thus, the bioactivity-guided fractionation was carried out, leading to the isolation of three related neolignan derivatives, identified as threo-austrobailignan-5 (1), threo-austrobailignan-6 (2), and threo-dihydroguaiaretic acid (3). Anti-T. cruzi activity of compounds 1-3 was performed against cell-derived trypomastigotes and intracellular amastigotes. Additionally, the mammalian cytotoxicity was investigated using NCTC cells. Compound 2 was the most effective against extracellular trypomastigotes with IC50 of 3.7 µM, while compound 3 showed activity in both clinically relevant forms of the parasite, trypomastigotes and amastigotes, with IC50 values of 7.0 and 16.2 µM, respectively. However, the structurally related compound 1 was inactive. Based on these results, compounds 2 and 3 were selected to evaluate the mechanism of cellular death. Compound 2 induced alteration in the plasma membrane permeability and consequently in the ROS levels after 120 min of incubation. By using flow cytometry and fluorescence microscopy, compound 3 showed alterations in the mitochondrial membrane potential (ΔΨm) of trypomastigotes. Considering the promising chemical and biological properties of neolignans 2 and 3, these compounds could be used as starting points to develop new lead compounds for Chagas disease.


Assuntos
Lignanas/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Saururaceae/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Brasil , Células Cultivadas , Guaiacol/análogos & derivados , Lignanas/isolamento & purificação , Macrófagos Peritoneais/parasitologia , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Tripanossomicidas/isolamento & purificação
20.
Biomed Res Int ; 2019: 8301569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355283

RESUMO

Chagas disease is a tropical illness caused by the protozoan Trypanosoma cruzi. The disease affects populations of the Americas and has been spread to other continents due to the migration process. The disease is partially controlled by two drugs, Benznidazole and Nifurtimox. These molecules are active in the acute phase of the infection but are usually ineffective during the symptomatic chronic phase. Several research groups have developed novel candidates to control Chagas disease; however, no novel commercial formulation is available. In this article, we described the anti-T. cruzi effects of phenothiazinium dyes in amastigote and trypomastigote forms of the parasite. Methylene Blue, New Methylene Blue, Toluidine Blue O, and 1,9-Dimethyl Methylene Blue inhibited the parasite proliferation at nanomolar concentrations and also demonstrated low toxicity in host cells. Moreover, combinations of phenothiazinium dyes indicated a synergic pattern against amastigotes compared to the Benznidazole counterparts. Phenothiazinium dyes levels of reactive oxygen species (ROS) and decreased the mitochondrial potential in trypomastigotes, indicating the mechanism of action of the dyes in T. cruzi. Our article offers a basis for future strategies for the control of Chagas disease using low-cost formulations, an important point for endemic underdeveloped regions.


Assuntos
Proliferação de Células/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Fenotiazinas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Doença de Chagas/parasitologia , Corantes/farmacologia , Humanos , Azul de Metileno/análogos & derivados , Azul de Metileno/farmacologia , Nifurtimox/farmacologia , Nitroimidazóis/farmacologia , Cloreto de Tolônio/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/patogenicidade
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