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1.
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
2.
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
3.
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
4.
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
5.
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
7.
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
8.
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
9.
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
10.
Curr Opin Chem Biol ; 67: 102127, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35248865

RESUMO

Potential use of metal complexes in medicine is an area of bioinorganic chemistry that has gained much interest. High-throughput omics approaches can provide in-depth insights into the mechanism of action of new metal-based compounds. Discovering new metallodrugs against Trypanosoma cruzi is an emerging field. Combining metallomics, proteomics, and transcriptomics allows the identification of multiple molecular targets and several parasitic metabolic pathways affected by V(IV), Pt(II), and Pd(II) potential antiparasitic drugs. Specifically, metallomics studies with Pd(II) and Pt(II) analogous compounds show higher parasite uptake of the Pt(II) than Pd(II), and both accumulate similarly in the parasite DNA fraction. Unexpectedly, vanadium did not associate with DNA. The studies reviewed illustrate the use of omics techniques for determining molecular targets of potential therapeutic agents.


Assuntos
Complexos de Coordenação , Tripanossomicidas , Trypanosoma cruzi , Antiparasitários/farmacologia , Complexos de Coordenação/química , DNA , Paládio/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia
11.
Mem Inst Oswaldo Cruz ; 117: e220004, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35293439

RESUMO

Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.


Assuntos
Doença de Chagas , Tripanossomicidas , Trypanosoma cruzi , Doença de Chagas/tratamento farmacológico , Humanos , América Latina , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
12.
Biomed Pharmacother ; 148: 112761, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35240521

RESUMO

The deficit of effective treatments for Chagas disease has led to searching for new substances with therapeutic potential. Natural products possess a wide variety of chemical structural motifs and are thus a valuable source of diverse lead compounds for the development of new drugs. Castanedia santamartensis is endemic to Colombia, and local indigenous communities often use it to treat skin sores from leishmaniasis; however, its mechanism of action against the infective form of Trypanosoma cruzi has not been determined. Thus, we performed chemical and biological studies of two alcoholic leaf extracts of C. santamartensis to identify their active fractions and relate them to a trypanocidal effect and evaluate their mechanism of action. Alcoholic extracts were obtained through cold maceration at room temperature and fractionated using classical column chromatography. Both ethanolic and methanolic extracts displayed activity against T. cruzi. Chemical studies revealed that kaurenoic acid was the major component of one fraction of the methanolic extract and two fractions of the ethanolic extract of C. santamartensis leaves. Moreover, caryophyllene oxide, kaurenol, taraxasterol acetate, pentadecanone, and methyl and ethyl esters of palmitate, as well as a group of phenolic compounds, including ferulic acid, caffeic acid, chlorogenic acid, myricetin, quercitrin, and cryptochlorogenic acid were identified in the most active fractions. Kaurenoic acid and the most active fractions CS400 and CS402 collapsed the mitochondrial membrane potential in trypomastigotes, demonstrating for the first time the likely mechanism against T. cruzi, probably due to interactions with other components of the fractions.


Assuntos
Asteraceae , Extratos Vegetais/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Diterpenos/química , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta
13.
Int J Mol Sci ; 23(5)2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35269985

RESUMO

The animal trypanosomiases are infections in a wide range of (domesticated) animals with any species of African trypanosome, such as Trypanosoma brucei, T. evansi, T. congolense, T. equiperdum and T. vivax. Symptoms differ between host and infective species and stage of infection and are treated with a small set of decades-old trypanocides. A complication is that not all trypanosome species are equally sensitive to all drugs and the reasons are at best partially understood. Here, we investigate whether drug transporters, mostly identified in T. b. brucei, determine the different drug sensitivities. We report that homologues of the aminopurine transporter TbAT1 and the aquaporin TbAQP2 are absent in T. congolense, while their introduction greatly sensitises this species to diamidine (pentamidine, diminazene) and melaminophenyl (melarsomine) drugs. Accumulation of these drugs in the transgenic lines was much more rapid. T. congolense is also inherently less sensitive to suramin than T. brucei, despite accumulating it faster. Expression of a proposed suramin transporter, located in T. brucei lysosomes, in T. congolense, did not alter its suramin sensitivity. We conclude that for several of the most important classes of trypanocides the presence of specific transporters, rather than drug targets, is the determining factor of drug efficacy.


Assuntos
Arsenicais , Tripanossomicidas , Trypanosoma congolense , Trypanosoma , Animais , Proteínas de Membrana Transportadoras , Pentamidina/metabolismo , Pentamidina/farmacologia , Suramina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/metabolismo
14.
AAPS J ; 24(3): 48, 2022 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-35338410

RESUMO

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Our aim was to assess (i) the efficacy of the eflornithine regimens in a time-to-event analysis and (ii) the feasibility of an L-eflornithine-based therapy integrating clinical and preclinical data. A pharmacodynamic time-to-event model was used to estimate the total dose of eflornithine, associated with 50% reduction in baseline hazard, when administered as monotherapy or in the nifurtimox-eflornithine combination therapy. The estimated total doses were 159, 60 and 291 g for intravenous eflornithine monotherapy, nifurtimox-eflornithine combination therapy and oral eflornithine monotherapy, respectively. Simulations suggested that L-eflornithine achieves a higher predicted median survival, compared to when racemate is administered, as treatment against late-stage gambiense human African trypanosomiasis. Our findings showed that oral L-eflornithine-based monotherapy would not result in adequate efficacy, even at high dose, and warrants further investigations to assess the potential of oral L-eflornithine-based treatment in combination with other treatments such as nifurtimox. An all-oral eflornithine-based regimen would provide easier access to treatment and reduce burden on patients and healthcare systems in gambiense human African trypanosomiasis endemic areas. Graphical abstract.


Assuntos
Tripanossomicidas , Tripanossomíase Africana , Animais , Quimioterapia Combinada , Eflornitina/farmacologia , Eflornitina/uso terapêutico , Humanos , Nifurtimox/efeitos adversos , Nifurtimox/uso terapêutico , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/epidemiologia
15.
Molecules ; 27(4)2022 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-35208983

RESUMO

Social insects are in mutualism with microorganisms, contributing to their resistance against infectious diseases. The fungus Pseudallescheria boydii SNB-CN85 isolated from termites produces ovalicin derivatives resulting from the esterification of the less hindered site of the ovalicin epoxide by long-chain fatty acids. Their structures were elucidated using spectroscopic analysis and semisynthesis from ovalicin. For ovalicin, these compounds displayed antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei, with IC50 values of 19.8 and 1.1 µM, respectively, for the most active compound, i.e., ovalicin linoleate. In parallel, metabolomic profiling of a collection of P. boydii strains associated with termites made it possible to highlight this class of compounds together with tyroscherin derivatives in all strains. Finally, the complete genome of P. boydii strains was obtained by sequencing, and the cluster of potential ovalicin and ovalicin biosynthesis genes was annotated. Through these metabolomic and genomic analyses, a new ovalicin derivative named boyden C, in which the 6-membered ring of ovalicin was opened by oxidative cleavage, was isolated and structurally characterized.


Assuntos
Antimaláricos , Isópteros/microbiologia , Plasmodium falciparum/crescimento & desenvolvimento , Scedosporium , Sesquiterpenos , Tripanossomicidas , Trypanosoma brucei brucei/crescimento & desenvolvimento , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Guiana Francesa , Scedosporium/química , Scedosporium/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia
16.
Eur J Med Chem ; 231: 114165, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-35144125

RESUMO

Chagas disease and leishmaniasis are two poverty-related neglected tropical diseases that cause high mortality and morbidity. Current treatments suffer from severe limitations and novel, safer and more effective drugs are urgently needed. Both Trypanosoma cruzi and Leishmania are auxotrophic for purines and absolutely depend on uptake and assimilation of host purines. This led us to successfully explore purine nucleoside analogues as chemotherapeutic agents against these and other kinetoplastid infections. This study extensively explored the modification of the 6-amino group of tubercidin, a natural product with trypanocidal activity but unacceptable toxicity for clinical use. We found that mono-substitution of the amine with short alkyls elicits potent and selective antitrypanosomal and antileishmanial activity. The methyl analogue 15 displayed the best in vitro activity against both T. cruzi and L. infantum and high selectivity versus host cells. Oral administration for five consecutive days in an acute Chagas disease mouse model resulted in significantly reduced peak parasitemia levels (75, 89 and 96% with 12.5, 25 and 50 mg/kg/day, respectively). as well as increased animal survival rates with the lower doses (83 and 67% for 12.5 and 25 mg/kg/day, respectively).


Assuntos
Doença de Chagas , Leishmania , Tripanossomicidas , Trypanosoma cruzi , Animais , Doença de Chagas/tratamento farmacológico , Camundongos , Nucleosídeos/farmacologia , Purinas/farmacologia , Purinas/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/farmacologia , Tripanossomicidas/uso terapêutico
17.
Molecules ; 27(4)2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35209185

RESUMO

Trypanosomiasis and leishmaniasis are among the major neglected diseases that affect poor people, mainly in developing countries. In Ethiopia, the latex of Aloe rugosifolia Gilbert & Sebsebe is traditionally used for the treatment of protozoal diseases, among others. In this study, the in vitro antitrypanosomal activity of the leaf latex of A. rugosifolia was evaluated against Trypanosoma congolense field isolate using in vitro motility and in vivo infectivity tests. The latex was also tested against the promastigotes of Leishmania aethiopica and L. donovani clinical isolates using alamar blue assay. Preparative thin-layer chromatography of the latex afforded a naphthalene derivative identified as plicataloside (2,8-O,O-di-(ß-D-glucopyranosyl)-1,2,8-trihydroxy-3-methyl-naphthalene) by means of spectroscopic techniques (HRESI-MS, 1H, 13C-NMR). Results of the study demonstrated that at 4.0 mg/mL concentration plicataloside arrested mobility of trypanosomes within 30 min of incubation period. Furthermore, plicataloside completely eliminated subsequent infectivity in mice for 30 days at concentrations of 4.0 and 2.0 mg/mL. Plicataloside also displayed antileishmanial activity against the promastigotes of L. aethopica and L. donovani with IC50 values 14.22 ± 0.41 µg/mL (27.66 ± 0.80 µM) and 18.86 ± 0.03 µg/mL (36.69 ± 0.06 µM), respectively. Thus, plicataloside may be used as a scaffold for the development of novel drugs effective against trypanosomiasis and leishmaniasis.


Assuntos
Aloe/química , Antiprotozoários/farmacologia , Látex/química , Extratos Vegetais/farmacologia , Antiprotozoários/química , Relação Dose-Resposta a Droga , Leishmania/efeitos dos fármacos , Estrutura Molecular , Extratos Vegetais/química , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia
18.
Bioorg Med Chem ; 58: 116577, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35189560

RESUMO

Chagas disease (CD) is a centenarian neglected parasitosis caused by the protozoan Trypanosoma cruzi (T. cruzi). Despite the continuous efforts of many organizations and institutions, CD is still an important human health problem worldwide. A lack of a safe and affordable treatment has led drug discovery programmes to focus, for years, on the search for molecules enabling interference with enzymes that are essential for T. cruzi survival. In this work, the authors want to offer a brief overview of the different validated targets that are involved in diverse parasite pathways: glycolysis, sterol synthesis, the de novo biosynthesis of pyrimidine nucleotides, the degradative processing of peptides and proteins, oxidative stress damage and purine salvage and nucleotide synthesis and metabolism. Their structural aspects, function, active sites, etc. were studied and considered with the aim of defining molecular bases in the search for new effective treatments for CD. This review also compiles, as much as possible, all the inhibitors reported to date against these T. cruzi targets, serving as a reference for future research in this field.


Assuntos
Doença de Chagas/tratamento farmacológico , Descoberta de Drogas , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Doença de Chagas/metabolismo , Humanos , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Tripanossomicidas/síntese química , Tripanossomicidas/química
19.
Phys Chem Chem Phys ; 24(8): 5052-5069, 2022 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-35144275

RESUMO

Chagas disease is a leading public health problem. More than 8 million people are affected by the disease, which is endemic in 21 countries in Latin America, generating an average annual cost of 7.2 billion dollars per year. The conventional treatment of Chagas disease is carried out by administering the drug benznidazole (BZN), which has caused numerous adverse reactions. Hence, the search for new, more efficient, and less toxic anti-chagasic agents is essential. Recently, chalcones have been researched to propose new therapies against neglected diseases, mainly Trypanosoma cruzi. The objective of this work was to evaluate for the first time the antiproliferative potential of chalcone derived from the natural product on T. cruzi strain Y. The molecular structure of the chalcone was confirmed by spectrometric data. The toxicity of chalcone in LLC-MK2 cells indicated that a concentration of 514.10 ± 62.40 µM was able to reduce cell viability by 50%. Regarding the effect of chalcone on epimastigote forms, an IC50 value of 46.57 ± 9.81 µM was observed; 45.92 ± 8.42 and 16.32 ± 3.41 µM at times of 24, 48 and 72 hours, respectively. The chalcone was able to eliminate trypomastigote forms at all concentrations tested, except for 31.25 µM, with LC50 values of 117.90 ± 12.60 µM, lower than the reference drug BZN (161.40 ± 31. 80 µM). The mechanism of action may be related to the membrane damage provoked by reduction of the mitochondrial potential. The anti-T. cruzi effect can be assigned through some structural aspects of the chalcone as the nitro group (NO2) is present, which can be enzymatically reduced forming a nitro radical, and the presence of methoxyl groups in the A ring of the chalcone. In silico studies showed that the chalcone had a higher affinity for cruzain when compared to BZN and the co-crystallized inhibitor KB2, as it presented a more thermodynamically stable complex in the order of -6.9 kcal mol-1. The pharmacokinetic prediction showed a significant probability of antiprotozoal activity, a good volume of distribution after being absorbed in the intestine, and a low chance of activity in the central nervous system. Therefore, these results suggest that the chalcone can become a potential cruzain enzyme inhibitor with trypanocidal activity.


Assuntos
Chalcona , Tripanossomicidas , Produtos Biológicos , Chalcona/farmacologia , Humanos , Simulação de Acoplamento Molecular , Tripanossomicidas/farmacologia , Trypanosoma cruzi/metabolismo
20.
J Inorg Biochem ; 229: 111726, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35065320

RESUMO

Leishmania amazonensis and L. braziliensis are the main etiological agents of the American Tegumentary Leishmaniasis (ATL). Taking into account the limited effectiveness and high toxicity of the current drug arsenal to treat ATL, novel options are urgently needed. Inspired by the fact that gold-based compounds are promising candidates for antileishmanial drugs, we studied the biological action of a systematic series of six (1)-(6) symmetric Au(I) benzyl and aryl-N-heterocyclic carbenes. All compounds were active at low micromolar concentrations with 50% effective concentrations ranging from 1.57 to 8.30 µM against Leishmania promastigotes. The mesityl derivative (3) proved to be the best candidate from this series, with a selectivity index ~13 against both species. The results suggest an effect of the steric and electronic parameters of the N-substituent in the activity. Intracellular infections were drastically reduced after 24h of (2)-(5) incubation in terms of infection rate and amastigote burden. Further investigations showed that our compounds induced significant parasites' morphological alterations and membrane permeability. Also, (3) and (6) were able to reduce the residual activity of three Leishmania recombinant cysteine proteases, known as possible targets for Au(I) complexes. Our promising results open the possibility of exploring gold complexes as leishmanicidal molecules to be further screened in in vivo models of infection.


Assuntos
Imidazóis/farmacologia , Compostos Organoáuricos/farmacologia , Tripanossomicidas/farmacologia , Animais , Membrana Celular/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Ouro/química , Imidazóis/síntese química , Leishmania braziliensis/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoáuricos/síntese química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tripanossomicidas/síntese química
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