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1.
Biomolecules ; 11(7)2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34356608

RESUMO

Anti-microbial peptides (AMPs), small biologically active molecules, produced by different organisms through their innate immune system, have become a considerable subject of interest in the request of novel therapeutics. Most of these peptides are cationic-amphipathic, exhibiting two main mechanisms of action, direct lysis and by modulating the immunity. The most commonly reported activity of AMPs is their anti-bacterial effects, although other effects, such as anti-fungal, anti-viral, and anti-parasitic, as well as anti-tumor mechanisms of action have also been described. Their anti-parasitic effect against leishmaniasis has been studied. Leishmaniasis is a neglected tropical disease. Currently among parasitic diseases, it is the second most threating illness after malaria. Clinical treatments, mainly antimonial derivatives, are related to drug resistance and some undesirable effects. Therefore, the development of new therapeutic agents has become a priority, and AMPs constitute a promising alternative. In this work, we describe the principal families of AMPs (melittin, cecropin, cathelicidin, defensin, magainin, temporin, dermaseptin, eumenitin, and histatin) exhibiting a potential anti-leishmanial activity, as well as their effectiveness against other microorganisms.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania/crescimento & desenvolvimento , Leishmaniose , Proteínas Citotóxicas Formadoras de Poros/uso terapêutico , Animais , Humanos , Leishmaniose/tratamento farmacológico , Leishmaniose/metabolismo , Leishmaniose/patologia , Malária/tratamento farmacológico , Malária/metabolismo , Malária/patologia
2.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443548

RESUMO

This work focuses on the search and development of drugs that may become new alternatives to the commercial drugs currently available for treatment of leishmaniasis. We have designed and synthesized 12 derivatives of bis(spiropyrazolone)cyclopropanes. We then characterized their potential application in therapeutic use. For this, the in vitro biological activities against three eukaryotic models-S. cerevisiae, five cancer cell lines, and the parasite L. mexicana-were evaluated. In addition, cytotoxicity against non-cancerous mammalian cells has been evaluated and other properties of interest have been characterized, such as genotoxicity, antioxidant properties and, in silico predictive adsorption, distribution, metabolism, and excretion (ADME). The results that we present here represent a first screening, indicating two derivatives of bis(spiropyrazolone)cyclopropanes as good candidates for the treatment of leishmaniasis. They have good specificity against parasites with respect to mammalian cells.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/química , Antiprotozoários/uso terapêutico , Linhagem Celular , Técnicas de Química Sintética , Ciclopropanos/química , Ciclopropanos/uso terapêutico , Desenho de Fármacos , Humanos , Leishmania/efeitos dos fármacos , Relação Estrutura-Atividade
3.
Turkiye Parazitol Derg ; 45(3): 227-229, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346882

RESUMO

Leishmaniasis is a protozoan parasitic disease transmitted to humans by infected female sand flies. Turkey has received more than three million immigrants from Syria because of the civil war and political instability. This study reported cases of two patients, who were from Syria and lived in Hatay, with cutaneous leishmaniasis and mucosal involvement. Two patients presented to the infectious diseases clinic with a complaint of facial lesions and were subsequently referred to the parasitology department laboratory. Smears were prepared from the lesions, stained with Giemsa and examined under a microscope. Moreover, aspirates taken from the patients' lesions were inoculated into the modified Novy-MacNeal-Nicolle medium. The diagnosis was made when amastigotes were detected in both smears. Proliferation of promastigotes was observed in one of the clinical specimens inoculated on the medium. By PZR-RFLP, Leishmania tropica were detected in the isolate. Both patients were treated with amphotericin B. One patient was treated again with a pentavalent antimony compound because of the recurrence of the lesion.


Assuntos
Antiprotozoários , Leishmania tropica , Leishmaniose Cutânea , Psychodidae , Animais , Antiprotozoários/uso terapêutico , Corantes Azur/uso terapêutico , Feminino , Humanos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico
4.
Front Cell Infect Microbiol ; 11: 700323, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34277476

RESUMO

Introduction: American tegumentary leishmaniasis (ATL), which can present as either cutaneous (CL) or mucosal leishmaniasis (ML), is endemic in South America, and first-line antimonial treatments are known for their wide range of adverse effects (AEs). Growing reports of drug resistance increase the urgency of the need for better treatment options. The objective of this pilot clinical trial was to assess the efficacy of and AEs associated with the oral combination of miltefosine and pentoxifylline based on a post hoc analysis. Methods: A pilot, randomized, open-label clinical trial was performed. The experimental group (M+P) received 50 mg twice a day (BID) miltefosine and 400 mg three times a day (TID) pentoxifylline, and the control group (A+P) received 20 mg Sb+V/kg/day intravenously and 400 mg TID pentoxifylline. Patients with ML received treatment for 28 days, and patients with CL received treatment for 20 days. Results: Forty-three patients were included: 25 with ML and 18 with CL caused by L.(V.) braziliensis. AEs were more frequent in the A+P group (p=0.322), and there was a need for treatment interruption due to severe AEs (p=0.027). Patients with CL had a higher chance of achieving a cure (p=0.042) and a higher risk of AEs (p=0.033). There was no difference in the chance of a cure based on the treatment (p=0.058). Conclusion: In this pilot randomized clinical trial, M+P treatment and A+P treatment yielded similar cure rates, and the former was associated with a lower risk of AEs. Future studies with more patients and longer follow-up are recommended.


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Pentoxifilina , Antiprotozoários/uso terapêutico , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Pentoxifilina/uso terapêutico , Fosforilcolina/análogos & derivados , Projetos Piloto , Resultado do Tratamento , Estados Unidos
5.
An Bras Dermatol ; 96(5): 602-604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34274187

RESUMO

Diffuse cutaneous leishmaniasis is a rare universal disease associated with an inadequate host cell immune response, caused by different species: infantum, aethiopica, major, mexicana, and others, which presents the challenge of a poor therapeutic response. In Brazil, it is caused by L. amazonensis. A case confirmed by histopathology with an abundance of vacuolated macrophages full of amastigotes and lymphocyte scarcity, identified by RFLP-ITS1PCR and in vitro decrease and exhaustion of the host cell immune response to L. amazonensis antigen, was treated early (3 months after the onset) with Glucantime (2 months) and allopurinol (29 months) with clinical cure, after a follow-up for 30 months after treatment.


Assuntos
Antiprotozoários , Leishmania mexicana , Leishmaniose Cutânea , Leishmaniose Tegumentar Difusa , Antiprotozoários/uso terapêutico , Brasil , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Tegumentar Difusa/tratamento farmacológico , Antimoniato de Meglumina
6.
Front Cell Infect Microbiol ; 11: 666746, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34150675

RESUMO

Antimonials continue to be considered the first-line treatment for leishmaniases, but its use entails a wide range of side effects and serious reactions. The search of new drugs requires the development of methods more sensitive and faster than the conventional ones. We developed and validated a fluorescence assay based in the expression of tdTomato protein by Leishmania, and we applied this method to evaluate the activity in vitro of flavonoids and reference drugs. The pIR1SAT/tdTomato was constructed and integrated into the genome of Leishmania (Leishmania) amazonensis. Parasites were selected with nourseothricin (NTC). The relation of L. amaz/tc3 fluorescence and the number of parasites was determined; then the growth in vitro and infectivity in BALB/c mice was characterized. To validate the fluorescence assay, the efficacy of miltefosine and meglumine antimoniate was compared with the conventional methods. After that, the method was used to assess in vitro the activity of flavonoids; and the mechanism of action of the most active compound was evaluated by transmission electron microscopy and ELISA. A linear correlation was observed between the emission of fluorescence of L. amaz/tc3 and the number of parasites (r2 = 0.98), and the fluorescence was stable in the absence of NTC. No differences were observed in terms of infectivity between L. amaz/tc3 and wild strain. The efficacy of miltefosine and meglumine antimoniate determined by the fluorescence assay and the microscopic test showed no differences, however, in vivo the fluorescence assay was more sensitive than limiting dilution assay. Screening assay revealed that the flavonoid galangin (GAL) was the most active compound with IC50 values of 53.09 µM and 20.59 µM in promastigotes and intracellular amastigotes, respectively. Furthermore, GAL induced mitochondrial swelling, lipid inclusion bodies and vacuolization in promastigotes; and up-modulated the production of IL-12 p70 in infected macrophages. The fluorescence assay is a useful tool to assess the anti-leishmanial activity of new compounds. However, the assay has some limitations in the macrophage-amastigote model that might be related with an interfere of flavanol aglycones with the fluorescence readout of tdTomato. Finally, GAL is a promising candidate for the development of new treatment against the leishmaniasis.


Assuntos
Antiprotozoários , Leishmania , Preparações Farmacêuticas , Animais , Antiprotozoários/uso terapêutico , Flavonoides , Proteínas Luminescentes , Camundongos , Camundongos Endogâmicos BALB C
7.
Exp Parasitol ; 226-227: 108124, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34139241

RESUMO

BACKGROUND: There is a necessity to develop or discover an alternative drug to combat the drug resistance by Giardia duodenalis and minimize the multiple doses and frequency of the conventional drug administration. Progressive repositioning or 'repurposing' of drugs has become widespread due to economic circumstances and medical emergency needs. Daflon 500 mg (DFL) is a natural product used safely as a nutrient supplement and an antidiabetic drug in many European countries and the US. OBJECTIVE: This study aimed at investigating the efficiency of DFL, in vivo, in a murine model as a safe alternative or co-drug for giardiasis. MATERIALS AND METHODS: Swiss Albino mice (n = 32) were inoculated with 1X104Giardia cysts and assigned to four groups: One group was the infected non-treated control mice and three experimental groups that were treated differently, either with Metronidazole (MTZ), DFL, or combined therapy of DFL/MTZ. Also, eight normal mice served as a control group. All mice were sacrificed 13 days post-infection for the parasitic, histopathological, and oxidative stress analysis. RESULTS: MTZ, DFL, and the combined therapy significantly reduced the number of trophozoites and cysts compared to their counterparts of the infected mice. The histopathological analysis of the small intestines of the mice treated with the combined therapy retained typical intestinal architecture and normal levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione. CONCLUSION: This study indicated promising actions of Daflon 500 as an anti-giardial drug, and the results demonstrated its potential effect in improving the intestinal epithelial tissue and disturbing the Giardia stages when it was taken collectively with Metronidazole.


Assuntos
Antiprotozoários/uso terapêutico , Diosmina/uso terapêutico , Giardíase/tratamento farmacológico , Metronidazol/uso terapêutico , Animais , Antiprotozoários/farmacologia , Diosmina/farmacologia , Combinação de Medicamentos , Fezes/parasitologia , Humanos , Intestinos/parasitologia , Intestinos/patologia , Metronidazol/farmacologia , Camundongos , Trofozoítos/efeitos dos fármacos
8.
Exp Parasitol ; 226-227: 108123, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34144040

RESUMO

The failures in the treatment of leishmaniasis is an increasing problem around the world, especially related to resistance. Thus, we describe the synthesis and in vivo anti-Leishmania activity of alkylphosphocholine and alkyltriazoles; besides, their likely action mechanisms stem from some eventual inhibition of parasite enzymes using computational tools. These compounds were tested in an in vivo hamster model infected with Leishmania Leishmania infantum chagasi. Fifty days after parasite inoculation, the two compounds 12-azidedodecylphosphocholine (3) and 3-(1-(12-fluorododecyl)-1H-1,2,3-triazol-1-yl)propano-1-ol (9), were separately administered once a day as oral suspensions (25 and 12.5 mg/kg/day, respectively) during ten days, and their efficacy was compared to the reference compound pentavalent antimonial Glucantime (GLU). Compound 3 significantly reduced the number of parasites in the spleen (4.93 × 102 amastigotes/g) and liver (4.52 × 103 amastigotes/g). Compound 9 reduced the number of amastigotes in the spleen to 1.30 × 104 and 1.36 × 103 amastigotes/g in the liver. GLU was the most effective overall treatment (7.50 × 101 and 2.28 × 102 amastigotes/g in the spleen and liver, respectively). The high activity levels of these compounds in vivo may stem from their high in vitro leishmanicidal activity and lipophilicity. The in silico absorption, distribution, metabolism, and excretion studies also showed some anti-Leishmania potential. Compound 9 had more lipophilic characteristics than those of compound 3. In silico studies of the nine enzymes of compounds 3 and 9 showed significant evidence of interactions with nicotimidase and tyrosine aminotransferase, demonstrating possible inhibition enzymes present in L. (L.) infantum chagasi. These compounds could be a promising template for developing a new class of leishmanicidal agents, by oral route, and deserve further investigation to explore different therapeutic regimens.


Assuntos
Antiprotozoários/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/farmacologia , Triazóis/farmacologia , Administração Oral , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Cricetinae , DNA Complementar/biossíntese , Feminino , Fígado/química , Mesocricetus , Simulação de Acoplamento Molecular , Fosforilcolina/administração & dosagem , Fosforilcolina/química , Fosforilcolina/uso terapêutico , RNA/isolamento & purificação , Baço/química , Triazóis/administração & dosagem , Triazóis/química , Triazóis/uso terapêutico
9.
Nanomedicine (Lond) ; 16(17): 1505-1518, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34189952

RESUMO

Background: Nanotechnology is a promising strategy to improve existing antileishmanial agents. Objective: To explore the evidence of encapsulated meglumine antimoniate for cutaneous leishmaniasis treatment in animal models. Materials & methods: The studies were recovered from PubMed, Scopus, EMBASE, LILACS, WoS and Google according to eligibility criteria following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Population, Intervention, Comparison, Outcomes and Study design (PICOS) strategy. Study appraisal was assessed using the Animal Research Reporting of In Vivo Experiments, SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) and Grading of Recommendations Assessment, Development and Evaluation (GRADE) recommendations. Results: Five studies were included. Liposomes, metallic and polymeric nanoparticles were tested in BALB/c mice against Leishmania major, L. tropica or L. amazonensis. Limitations: Few studies were found to meet the eligibility criteria. Conclusion: All formulations had a significant efficacy, similar to the meglumine antimoniate reference treatment concerning the lesion size and parasite burden. The studies had a high and moderate risk of bias, and the confidence in cumulative evidence was considered low. Therefore, we encourage the development of high-quality preclinical studies. Registration: PROSPERO register CRD42020170191.


Assuntos
Antiprotozoários , Leishmaniose Cutânea , Nanopartículas , Animais , Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos BALB C
10.
Int J Pharm ; 605: 120761, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34081999

RESUMO

Leishmaniasis is a prevalent parasitic infection belonging to neglected tropical diseases. It is caused by Leishmania protozoan parasites transmitted by sandflies and it is responsible for increased morbidity/mortality especially in low- and middle-income countries. The lack of cheap, portable, easy to use diagnostic tools exhibiting high efficiency and specificity impede the early diagnosis of the disease. Furthermore, the typical anti-leishmanial agents are cytotoxic, characterized by low patient compliance and require long-term regimen and usually hospitalization. In addition, due to the intracellular nature of the disease, the existing treatments exhibit low bioavailability resulting in low therapeutic efficacy. The above, combined with the common development of resistance against the anti-leishmanial agents, denote the urgent need for novel therapeutic strategies. Furthermore, the lack of effective prophylactic vaccines hinders the control of the disease. The development of nanoparticle-based biosensors and nanocarrier-aided treatment and vaccination strategies could advance the diagnosis, therapy and prevention of leishmaniasis. The present review intends to highlight the various nanotechnology-based approaches pursued until now to improve the detection of Leishmania species in biological samples, decrease the side effects and increase the efficacy of anti-leishmanial drugs, and induce enhanced immune responses, specifically focusing on the outcome of their preclinical and clinical evaluation.


Assuntos
Antiprotozoários , Leishmania , Leishmaniose , Nanopartículas , Vacinas , Antiprotozoários/uso terapêutico , Humanos , Leishmaniose/diagnóstico , Leishmaniose/tratamento farmacológico , Leishmaniose/prevenção & controle , Nanotecnologia
11.
J Med Microbiol ; 70(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34115583

RESUMO

Introduction. Leishmaniasis is a neglected tropical and subtropical disease caused by over 20 protozoan species.Hypothesis. Treatment of this complex disease with traditional synthetic drugs is a major challenge worldwide. Natural constituents are unique candidates for future therapeutic development.Aim. This study aimed to assess the in vivo anti-leishmanial effect of the Gossypium hirsutum extract, and its fractions compared to the standard drug (Glucantime, MA) in a murine model and explore the mechanism of action.Methodology. Footpads of BALB/c mice were infected with stationary phase promastigotes and treated topically and intraperitoneally with G. hirsutum extract, its fractions, or Glucantime, 4 weeks post-infection. The extract and fractions were prepared using the Soxhlet apparatus with chloroform followed by the column procedure.Results. The crude extract significantly decreased the footpad parasite load and lesion size compared to the untreated control group (P<0.05), as revealed by dilution assay, quantitative real-time PCR, and histopathological analyses. The primary mode of action involved an immunomodulatory role towards the Th1 response in the up-regulation of IFN-γ and IL-12 and the suppression of IL-10 gene expression profiling against cutaneous leishmaniasis caused by Leishmania major.Conclusion. This finding suggests that the extract possesses multiple combinatory effects of diverse bioactive phytochemical compositions that exert its mechanisms of action through agonistic-synergistic interactions. The topical extract formulation could be a suitable and unique candidate for future investigation and pharmacological development. Further studies are crucial to evaluate the therapeutic potentials of the extract alone and in combination with conventional drugs using clinical settings.


Assuntos
Antiprotozoários/uso terapêutico , Gossypium , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Fitoterapia , Extratos Vegetais/uso terapêutico , Administração Tópica , Animais , Antiprotozoários/farmacologia , Feminino , Injeções Intraperitoneais , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/genética , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/metabolismo , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Leishmaniose Cutânea/fisiopatologia , Linfonodos/patologia , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Baço/parasitologia , Baço/patologia , Células Th1/imunologia , Transcriptoma
12.
PLoS Negl Trop Dis ; 15(5): e0009460, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34048461

RESUMO

BACKGROUND: Cutaneous leishmaniasis (CL) in Ethiopia, caused by Leishmania aethiopica, is often severe and hard to treat compared to CL caused by other species elsewhere. Miltefosine is the only oral anti-leishmanial drug, with a favorable side-effect profile compared to routinely available sodium stibogluconate (SSG), but evidence about its use for L. aethiopica is lacking. METHODOLOGY AND PRINCIPAL FINDINGS: In an observational cohort study, treatment outcomes, safety and adherence among CL patients who required systemic treatment and received miltefosine for 28 days in Boru Meda Hospital and University of Gondar Hospital were studied. Patient cure was defined as 100% flattening for non-ulcerated lesions and 100% flattening and 100% re-epithelization for ulcerated lesions. Outcomes were documented for day 28, 90 and 180, both per site, and pooled, adjusting for site as a fixed effect with effect coding. Among 94 included patients (32 in Gondar, 62 in Boru Meda), median lesion duration was 12 months, median size six cm, and mucosal involvement (46.8%) and diffuse (30.9%) lesions were common. Adherence to miltefosine was good, and side-effects were tolerable. Initial outcomes at day 28 were promising, with 68.8% and 94.0% of patients having good improvement or cure in Gondar and Boru Meda respectively. In Boru Meda, outcomes were good with 72.7% and 72.9% cure at day 90 and day 180 respectively. In Gondar, results were less promising, with only 12.5% and 26.7% cure at day 90 and day 180, although confidence intervals were wide. In pooled estimates, 48.7% of patients reached cure at day 180, and 32.3% relapsed. Outcomes were better in Boru Meda Hospital, for smaller lesions and for mucosal lesions. CONCLUSIONS/SIGNIFICANCE: Based on miltefosine's good initial response, tolerable side-effects, tablet-form, we propose to include miltefosine for future clinical trials using extended treatment schedules, combination therapy, or targeting specific subgroups. TRIAL REGISTRATION: ClinicalTrials.gov NCT04004754.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Fosforilcolina/análogos & derivados , Administração Oral , Adolescente , Adulto , Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Estudos de Coortes , Etiópia , Feminino , Humanos , Leishmania/efeitos dos fármacos , Masculino , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/uso terapêutico , Projetos Piloto , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Resultado do Tratamento
14.
J Med Chem ; 64(10): 6608-6620, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33974434

RESUMO

Trichomonas vaginalis causes the most common, nonviral sexually transmitted infection. Only metronidazole (Mz) and tinidazole are approved for treating trichomoniasis, yet resistance is a clinical problem. The gold(I) complex, auranofin, is active against T. vaginalis and other protozoa but has significant human toxicity. In a systematic structure-activity exploration, we show here that diversification of gold(I) complexes, particularly as halides with simple C1-C3 trialkyl phosphines or as bistrialkyl phosphine complexes, can markedly improve potency against T. vaginalis and selectivity over human cells compared to that of the existing antirheumatic gold(I) drugs. All gold(I) complexes inhibited the two most abundant isoforms of the presumed target enzyme, thioredoxin reductase, but a subset of compounds were markedly more active against live T. vaginalis than the enzyme, suggesting that alternative targets exist. Furthermore, all tested gold(I) complexes acted independently of Mz and were able to overcome Mz resistance, making them candidates for the treatment of Mz-refractory trichomoniasis.


Assuntos
Antiprotozoários/química , Complexos de Coordenação/química , Ouro/química , Fosfinas/química , Animais , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Parasitária , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Tiorredoxina Dissulfeto Redutase/metabolismo , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trofozoítos/efeitos dos fármacos
15.
Biomed Pharmacother ; 139: 111566, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33839494

RESUMO

BACKGROUND: In recent years, magnetic nanoparticles (NMP) as novel materials have been widely used for biomedical, diagnostic and therapeutic purposes like microbial infection therapy. The purpose of this study is to synthesize PO coated iron oxide magnetic nanoparticles (Fe3O4@PO NPs) and their anti-leishmanial effects in vitro and in vivo against cutaneous leishmaniasis. METHODS: Fe3O4 magnetic nanoparticles were synthesized by the coprecipitation of Fe2 + and Fe3 + ions and used as a nanocarrier for the production of Fe3O4@PO NPs. The in vitro antileishmanial effects of PO-coated Fe3O4 NPs and Fe3O4 NPs (10-200 µg/mL) was determined against the intracellular amastigotes of Leishmania major (MRHO/IR/75/ER) and, then, examined on cutaneous leishmaniasis induced in male BALB/c mice by L. major. The rate of infectivity, production of nitric oxide (NO), and cytotoxic activates of Fe3O4 NPs and Fe3O4@PO NPs on J774-A1 macrophage cells were determined. RESULTS: The size scattering of the Fe3O4 NPs and Fe3O4@PO NPs were in the range among 1-40 and 5-55 nm, respectively. The obtained IC50 values were 62.3 ± 2.15 µg/mL, 31.3 ± 2.26 µg/mL, and 52.6 ± 2.15 µg/mL for the Fe3O4 NPs and Fe3O4@PO NPs, and MA, respectively. The results revealed that the mean number of parasites and the mean diameter of the lesions was considerably (p < 0.05) decreased in the infected mice treated with Fe3O4 NPs and Fe3O4@PO NPs. The Fe3O4 NPs and Fe3O4@PO NPs significantly (p < 0.05) prompted the production of NO as a dose-dependent manner. The promastigotes pre-incubated in Fe3O4 NPs and Fe3O4@PO NPs at the concentration of 5 µg/mL had the ability to infect only 41.7% and 28.3% of the macrophages cells. The selectivity index of greater than 10 for Fe3O4 NPs and Fe3O4@PO NPs showed its safety to the J774-A1 macrophage cells and specificity to the parasite. CONCLUSION: The results of this survey indicated the high potency of Fe3O4@PO NPs to inhibit the growth of amastigote forms of L. major as well as recovery and improvement CL induced by L. major in BALB/c mice without significant cytotoxicity. The results also indicated that, although the possible anti-leishmanial mechanisms of Fe3O4@PO NPs have not been clearly understood, however, the triggering of NO may be considered as one of the possible anti-leishmanial mechanisms of these nanoparticles. However, additional studies, in particular in clinical contexts, are mandatory.


Assuntos
Antiprotozoários/uso terapêutico , Etanolaminas/química , Óxido Ferroso-Férrico/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas de Magnetita/uso terapêutico , Piridonas/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Portadores de Fármacos , Combinação de Medicamentos , Óxido Ferroso-Férrico/administração & dosagem , Óxido Ferroso-Férrico/química , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/parasitologia , Macrófagos/parasitologia , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese
16.
Antimicrob Agents Chemother ; 65(7): e0151320, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33903112

RESUMO

Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, making the need for more effective, safer, and less expensive drugs an urgent one. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in-house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, Leishmania amazonensis, and Leishmania major. Several of the screened compounds showed half-maximal inhibitory concentrations (IC50s) against intracellular L. infantum parasites in the submicromolar range (compounds 1h, IC50 = 0.9 µM, and 1n, IC50 = 0.7 µM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major parasites, albeit in the low micromolar range. Mechanistic studies revealed that compound 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that compound 1n is a promising antileishmanial lead and emphasizes the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.


Assuntos
Antiprotozoários , Leishmania mexicana , Leishmaniose , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Iminas/uso terapêutico , Leishmaniose/tratamento farmacológico , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C
17.
Lancet Infect Dis ; 21(8): 1141-1150, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33836157

RESUMO

BACKGROUND: Assessment of therapeutic response with standard serological diagnostic assays in patients with chronic Chagas disease is a major challenge due to the long persistence of parasite-specific antibodies. The current consensus for parasitological cure is to monitor conversion from positive to negative Trypanosoma cruzi serology (seroreversion). However, because of robust humoral immune response, seroreversion by standard serological tests can take years to decades. Developing novel tests of parasitological cure or surrogates is thus a priority in the Chagas disease field. We aimed to evaluate the MultiCruzi assay as a predictive tool for parasitological cure in a cohort of treated infants and children with acute and chronic Chagas disease enrolled in a long-term retrospective longitudinal study with clinical, serological, and parasitological follow-up, and to explore whether MultiCruzi could predict parasitological cure more quickly than the current reference method. METHODS: Patients from two retrospective paediatric Chagas disease cohort studies with clinical, serological, and parasitological follow-up, diagnosed and treated at the parasitology service, Hospital de Niños Ricardo Gutierrez (Buenos Aires, Argentina) were included in this retrospective cohort study. Serum samples were collected every 6 months to 12 months between Oct 22, 1990, and June 3, 2019, for cohort 1 and 1 month after birth for cohort 2 and then every 3 months for a year between July 23, 2012, and April 19, 2016. We evaluated serological follow-up with the Chagatest ELISA (Wiener Lab, Rosario, Argentina) and used this as a clinical reference method for the evaluation of seroreversion. We compared Chagatest ELISA results with results of MultiCruzi (InfYnity Biomarkers, Lyon, France), a novel antibody profiling multiplex assay, investigating seroreversion events with both of the assays and prediction of seroreversion with MultiCruzi using an interpretation formula. FINDINGS: Combining experimental data from discrete analysis of 15 T cruzi antigens efficiently predicted seroreversion at an early stage, which was later confirmed by conventional T cruzi serology. In cohort 1 (n=69), which included children of three different age groups, we observed differences 2 years after therapy. In the 27 individuals from cohort 1 who were treated within the first 12 months of age, MultiCruzi predicted early seroreversion in 21 (78%) patients whereas nine (33%) patients showed seroreversion with Chagatest ELISA (seroreversion difference 0·44, 95% CI 0·26-0·63; p=0·0005). In the 12 patients from cohort 1 treated between 1 year and 2 years of age, MultiCruzi predicted early seroreversion in six (50%) patients, whereas only one (8%) patient was confirmed to be seronegative with Chagatest ELISA (seroreversion difference 0·42, 95% CI 0·14-0·70; p=0·0253). In the 30 patients from cohort 1 who were treated between 2 years and 19 years of age, MultiCruzi predicted early seroreversion in five (6%) patients, whereas no patients were found to be seronegative with Chagatest ELISA (seroreversion difference 0·17, 0·03-0·30; p=0·0253). In cohort 2 (n=27), which included only children younger than 1 year of age and had a shorter follow up (between 5 months and 32 months), the proportion of reported events was significantly different 180 days after treatment for the T cruzi-positive group (early seroreversion predicted in nine [90%] of ten patients with MultiCruzi and confirmed seroreversion in four [40%] of ten patients with Chagatest ELISA; seroreversion difference 0·50, 95% CI 0·19-0·81; p=0·0253) and for the T cruzi-negative group 90 days (early seroreversion predicted in five [29%] of 17 patients with MultiCruzi and confirmed seroreversion in one [6%] of 17 patients with Chagatest ELISA; seroreversion difference 0·24, 0·03-0·44; p=0·0455) and 180 days (early seroreversion predicted in 17 [100%] of 17 patients with MultiCruzi and confirmed seroreversion only in seven [41%] of 17 patients with Chagatest ELISA; seroreversion difference 0·59, 0·35-0·82; p=0·0016) after treatment. INTERPRETATION: The MultiCruzi assay can be used as a predictive monitoring tool to assess parasitological cure in children. This approach might be a solution to forecast forthcoming seroreversion in treated adults infected with T cruzi, but this requires further investigation. FUNDING: Drugs for Neglected Diseases initiative. TRANSLATIONS: For the Spanish, Portuguese and French translations of the abstract see Supplementary Materials section.


Assuntos
Anticorpos Antiprotozoários/sangue , Antiprotozoários/uso terapêutico , Doença de Chagas/tratamento farmacológico , Testes Sorológicos/métodos , Trypanosoma cruzi/imunologia , Adolescente , Formação de Anticorpos , Argentina , Criança , Pré-Escolar , Monitoramento de Medicamentos , Feminino , França , Humanos , Lactente , Estimativa de Kaplan-Meier , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Trypanosoma cruzi/genética , Trypanosoma cruzi/isolamento & purificação , Adulto Jovem
18.
Int J Dermatol ; 60(9): 1109-1113, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33846973

RESUMO

BACKGROUND: We compared demographic, clinical, treatment, and outcome characteristics of facial cutaneous leishmaniasis (CL) and non-facial CL. METHODS: In this retrospective cohort study, polymerase chain reaction confirmed Leishmania major CL patients with ≥2 documented hospital visits, 2014-2019, were included. RESULTS: Overall, 134 patients (34% and 66% with facial and non-facial CL, respectively) were included. Facial CL patients were younger (43% vs. 8% <18 years, P < 0.001), with a higher proportion of females (41% vs. 25%, P = 0.07) compared with non-facial CL. Clinical characteristics, including number and size of lesions and ulcer appearance, were similar in both the groups. Higher paromomycin/methylbenzethonium chloride ointment treatment rates were noted in facial CL (85% vs. 64%, P = 0.02). Intralesional sodium stibogluconate was given to 41% and 53% of facial CL and non-facial CL patients, respectively (P = 0.21). Cryotherapy and surgery were only used in non-facial CL patients (5% and 1% of all CL cases, respectively). Systemic treatment (oral miltefosine, intravenous [IV] sodium stibogluconate, IV liposomal amphotericin B) was used in <5% of the cases in both the groups. Overall, 84% of patients showed signs of improvement, including decreased lesion size or clinical improvement in 73% and 75% of patients, respectively. Only 5% of all cases healed without scarring. Outcome rates were similar in both groups. CONCLUSIONS: Facial CL patients were younger and received more frequently Leishmania-specific topical treatment than non-facial CL patients. In contrast, the two groups were similar regarding clinical characteristics and outcome. These findings suggest differences in disease severity perception by patients and physicians.


Assuntos
Antiprotozoários , Leishmania major , Leishmaniose Cutânea , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Feminino , Humanos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Estudos Retrospectivos
19.
J Med Chem ; 64(9): 5905-5930, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904304

RESUMO

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.


Assuntos
Desenho de Fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Proteínas de Protozoários/metabolismo , Animais , Antiprotozoários/química , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Sítios de Ligação , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/metabolismo , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Camundongos , Simulação de Dinâmica Molecular , Complexo de Endopeptidases do Proteassoma/química , Inibidores de Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Inibidores de Proteassoma/uso terapêutico , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Proteínas de Protozoários/química , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade
20.
Prog Chem Org Nat Prod ; 115: 115-176, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33797642

RESUMO

Secondary metabolites (SM) from organisms have served medicinal chemists over the past two centuries as an almost inexhaustible pool of new drugs, drug-like skeletons, and chemical probes that have been used in the "hunt" for new biologically active molecules with a "beneficial effect on human mind and body." Several secondary metabolites, or their derivatives, have been found to be the answer in the quest to search for new approaches to treat or even eradicate many types of diseases that oppress humanity. A special place among SM is occupied by lignans and neolignans. These phenolic compounds are generated biosynthetically via radical coupling of two phenylpropanoid monomers, and are known for their multitarget activity and low toxicity. The disadvantage of the relatively low specificity of phenylpropanoid-based SM turns into an advantage when structural modifications of these skeletons are made. Indeed, phenylpropanoid-based SM previously have proven to offer great potential as a starting point in drug development. Compounds such as Warfarin® (a coumarin-based anticoagulant) as well as etoposide and teniposide (podophyllotoxin-based anticancer drugs) are just a few examples. At the beginning of the third decade of the twenty-first century, the call for the treatment of more than a dozen rare or previously "neglected" diseases remains for various reasons unanswered. Leishmaniasis, a neglected disease that desperately needs new ways of treatment, is just one of these. This disease is caused by more than 20 leishmanial parasites that are pathogenic to humans and are spread by as many as 800 sandfly species across subtropical areas of the world. With continuing climate changes, the presence of Leishmania parasites and therefore leishmaniasis, the disease caused by these parasites, is spreading from previous locations to new areas. Thus, leishmaniasis is affecting each year a larger proportion of the world's population. The choice of appropriate leishmaniasis treatment depends on the severity of the disease and its form of manifestation. The success of current drug therapy is often limited, due in most cases to requiring long hospitalization periods (weeks to months) and the toxicity (side effects) of administered drugs, in addition to the increasing resistance of the parasites to treatment. It is thus important to develop new drugs and treatments that are less toxic, can overcome drug resistance, and require shorter periods of treatment. These aspects are especially important for the populations of developing countries. It was reported that several phenylpropanoid-based secondary metabolites manifest interesting antileishmanial activities and are used by various indigenous people to treat leishmaniasis. In this chapter, the authors shed some light on the various biological activities of phenylpropanoid natural products, with the main focus being on their possible applications in the context of antileishmanial treatment.


Assuntos
Antiprotozoários , Leishmaniose , Lignanas , Preparações Farmacêuticas , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Humanos , Leishmaniose/tratamento farmacológico , Lignanas/farmacologia , Lignanas/uso terapêutico , Fenóis/farmacologia , Fenóis/uso terapêutico
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