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[PMID]:29326050
[Au] Autor:Nayak A; Akpunarlieva S; Barrett M; Burchmore R
[Ad] Endereço:Institute of Infection, Immunity and Inflammation and Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
[Ti] Título:A defined medium for Leishmania culture allows definition of essential amino acids.
[So] Source:Exp Parasitol;185:39-52, 2018 Feb.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Axenic culture of Leishmania is generally performed in rich, serum-supplemented media which sustain robust growth over multiple passages. The use of such undefined media, however, obscures proteomic analyses and confounds the study of metabolism. We have established a simple, defined culture medium that supports the sustained growth of promastigotes over multiple passages and which yields parasites that have similar infectivity to macrophages to parasites grown in a conventional semi-defined medium. We have exploited this medium to investigate the amino acid requirements of promastigotes in culture and have found that phenylalanine, tryptophan, arginine, leucine, lysine and valine are essential for viability in culture. Most of the 20 proteogenic amino acids promote growth of Leishmania promastigotes, with the exception of alanine, asparagine, and glycine. This defined medium will be useful for further studies of promastigote substrate requirements, and will facilitate future proteomic and metabolomic analyses.
[Mh] Termos MeSH primário: Aminoácidos Essenciais/metabolismo
Meios de Cultura/química
Leishmania/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Anfotericina B/farmacologia
Animais
Antiprotozoários/farmacologia
Concentração Inibidora 50
Leishmania/efeitos dos fármacos
Leishmania donovani/crescimento & desenvolvimento
Leishmania major/crescimento & desenvolvimento
Leishmania mexicana/crescimento & desenvolvimento
Metotrexato/farmacologia
Pentamidina/farmacologia
Inoculações Seriadas
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Essential); 0 (Antiprotozoal Agents); 0 (Culture Media); 673LC5J4LQ (Pentamidine); 7XU7A7DROE (Amphotericin B); YL5FZ2Y5U1 (Methotrexate)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE


  2 / 1547 MEDLINE  
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[PMID]:29287089
[Au] Autor:Ortiz D; Guiguemde WA; Hammill JT; Carrillo AK; Chen Y; Connelly M; Stalheim K; Elya C; Johnson A; Min J; Shelat A; Smithson DC; Yang L; Zhu F; Guy RK; Landfear SM
[Ad] Endereço:Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon, United States of America.
[Ti] Título:Discovery of novel, orally bioavailable, antileishmanial compounds using phenotypic screening.
[So] Source:PLoS Negl Trop Dis;11(12):e0006157, 2017 12.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid binding dye SYBR Green I. This screen identified approximately 2,700 compounds that inhibited growth by over 65% at a single point concentration of 10 µM. We next used this 2700 compound focused library to identify compounds that were highly potent against the disease-causing intra-macrophage amastigote form and exhibited limited toxicity toward the host macrophages. This two-step screening strategy uncovered nine unique chemical scaffolds within our collection, including two previously described antileishmanials. We further profiled two of the novel compounds for in vitro absorption, distribution, metabolism, excretion, and in vivo pharmacokinetics. Both compounds proved orally bioavailable, affording plasma exposures above the half-maximal effective concentration (EC50) concentration for at least 12 hours. Both compounds were efficacious when administered orally in a murine model of cutaneous leishmaniasis. One of the two compounds exerted potent activity against trypanosomes, which are kinetoplastid parasites related to Leishmania species. Therefore, this compound could help control multiple parasitic diseases. The promising pharmacokinetic profile and significant in vivo efficacy observed from our HTS hits highlight the utility of our two-step phenotypic screening strategy and strongly suggest that medicinal chemistry optimization of these newly identified scaffolds will lead to promising candidates for an orally available anti-parasitic drug.
[Mh] Termos MeSH primário: Antiprotozoários/farmacocinética
Avaliação Pré-Clínica de Medicamentos/métodos
Leishmania mexicana/efeitos dos fármacos
Leishmaniose Cutânea/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Oral
Animais
Antiprotozoários/administração & dosagem
Antiprotozoários/efeitos adversos
Antiprotozoários/química
Linhagem Celular
Química Farmacêutica
Descoberta de Drogas
Feminino
Seres Humanos
Leishmania mexicana/crescimento & desenvolvimento
Leishmaniose Cutânea/parasitologia
Macrófagos/parasitologia
Camundongos
Camundongos Endogâmicos BALB C
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiprotozoal Agents)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0006157


  3 / 1547 MEDLINE  
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[PMID]:29191699
[Au] Autor:Nieto-Meneses R; Castillo R; Hernández-Campos A; Maldonado-Rangel A; Matius-Ruiz JB; Trejo-Soto PJ; Nogueda-Torres B; Dea-Ayuela MA; Bolás-Fernández F; Méndez-Cuesta C; Yépez-Mulia L
[Ad] Endereço:Departamento de Parasitología, ENCB-IPN, 11340 Mexico City, Mexico; Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias-Pediatría, Instituto Mexicano del Seguro Social, 06720 Mexico City, Mexico.
[Ti] Título:In vitro activity of new N-benzyl-1H-benzimidazol-2-amine derivatives against cutaneous, mucocutaneous and visceral Leishmania species.
[So] Source:Exp Parasitol;184:82-89, 2018 Jan.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The identification of specific therapeutic targets and the development of new drugs against leishmaniasis are urgently needed, since chemotherapy currently available for its treatment has several problems including many adverse side effects. In an effort to develop new antileishmanial drugs, in the present study a series of 28 N-benzyl-1H-benzimidazol-2-amine derivatives was synthesized and evaluated in vitro against Leishmania mexicana promastigotes. Compounds 7 and 8 with the highest antileishmanial activity (micromolar) and lower cytotoxicity than miltefosine and amphotericin B were selected to evaluate their activity against L. braziliensis 9and L. donovani, species causative of mucocutaneous and visceral leishmaniasis, respectively. Compound 7 showed significantly higher activity against L. braziliensis promastigotes than compound 8 and slightly lower than miltefosine. Compounds 7 and 8 had IC values in the micromolar range against the amastigote of L. mexicana and L. braziliensis. However, both compounds did not show better activity against L. donovani than miltefosine. Compound 8 showed the highest SI against both parasite stages of L. mexicana. In addition, compound 8 inhibited 68.27% the activity of recombinant L. mexicana arginase (LmARG), a therapeutic target for the treatment of leishmaniasis. Docking studies were also performed in order to establish the possible mechanism of action by which this compound exerts its inhibitory effect. Compound 8 shows promising potential for the development of more potent antileishmanial benzimidazole derivatives.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Benzimidazóis/farmacologia
Leishmania braziliensis/efeitos dos fármacos
Leishmania donovani/efeitos dos fármacos
Leishmania mexicana/efeitos dos fármacos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Anfotericina B/farmacologia
Animais
Antiprotozoários/toxicidade
Arginase/antagonistas & inibidores
Arginase/química
Benzimidazóis/síntese química
Benzimidazóis/química
Benzimidazóis/toxicidade
Linhagem Celular
Concentração Inibidora 50
Leishmania mexicana/enzimologia
Leishmaniose Cutânea/tratamento farmacológico
Leishmaniose Cutânea/parasitologia
Leishmaniose Mucocutânea/tratamento farmacológico
Leishmaniose Mucocutânea/parasitologia
Leishmaniose Visceral/tratamento farmacológico
Leishmaniose Visceral/parasitologia
Macrófagos/efeitos dos fármacos
Camundongos
Simulação de Acoplamento Molecular
Fosforilcolina/análogos & derivados
Fosforilcolina/farmacologia
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Benzimidazoles); 107-73-3 (Phosphorylcholine); 53EY29W7EC (miltefosine); 7XU7A7DROE (Amphotericin B); EC 3.5.3.1 (Arginase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171202
[St] Status:MEDLINE


  4 / 1547 MEDLINE  
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[PMID]:29077741
[Au] Autor:Aoki JI; Muxel SM; Zampieri RA; Laranjeira-Silva MF; Müller KE; Nerland AH; Floeter-Winter LM
[Ad] Endereço:Department of Physiology, Institute of Bioscience, University of Sao Paulo, Sao Paulo, Brazil.
[Ti] Título:RNA-seq transcriptional profiling of Leishmania amazonensis reveals an arginase-dependent gene expression regulation.
[So] Source:PLoS Negl Trop Dis;11(10):e0006026, 2017 Oct.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Leishmania is a protozoan parasite that alternates its life cycle between the sand-fly vector and the mammalian host. This alternation involves environmental changes and leads the parasite to dynamic modifications in morphology, metabolism, cellular signaling and regulation of gene expression to allow for a rapid adaptation to new conditions. The L-arginine pathway in L. amazonensis is important during the parasite life cycle and interferes in the establishment and maintenance of the infection in mammalian macrophages. Host arginase is an immune-regulatory enzyme that can reduce the production of nitric oxide by activated macrophages, directing the availability of L-arginine to the polyamine pathway, resulting in parasite replication. In this work, we performed transcriptional profiling to identify differentially expressed genes in L. amazonensis wild-type (La-WT) versus L. amazonensis arginase knockout (La-arg-) promastigotes and axenic amastigotes. METHODOLOGY/PRINCIPAL FINDINGS: A total of 8253 transcripts were identified in La-WT and La-arg- promastigotes and axenic amastigotes, about 60% of them codifying hypothetical proteins and 443 novel transcripts, which did not match any previously annotated genes. Our RNA-seq data revealed that 85% of genes were constitutively expressed. The comparison of transcriptome and metabolome data showed lower levels of arginase and higher levels of glutamate-5-kinase in La-WT axenic amastigotes compared to promastigotes. The absence of arginase activity in promastigotes increased the levels of pyrroline 5-carboxylate reductase, but decreased the levels of arginosuccinate synthase, pyrroline 5-carboxylate dehydrogenase, acetylornithine deacetylase and spermidine synthase transcripts levels. These observations can explain previous metabolomic data pointing to the increase of L-arginine, citrulline and L-glutamate and reduction of aspartate, proline, ornithine and putrescine. Altogether, these results indicate that arginase activity is important in Leishmania gene expression modulation during differentiation and adaptation to environmental changes. Here, we confirmed this hypothesis with the identification of differential gene expression of the enzymes involved in biosynthesis of amino acids, arginine and proline metabolism and arginine biosynthesis. CONCLUSIONS/SIGNIFICANCE: All data provided information about the transcriptomic profiling and the expression levels of La-WT and La-arg- promastigotes and axenic amastigotes. These findings revealed the importance of arginase in parasite survival and differentiation, and indicated the existence of a coordinated response in the absence of arginase activity related to arginine and polyamine pathways.
[Mh] Termos MeSH primário: Arginase/metabolismo
Regulação da Expressão Gênica
Leishmania mexicana/genética
Análise de Sequência de RNA
[Mh] Termos MeSH secundário: Arginase/genética
Arginina/biossíntese
Arginina/metabolismo
Expressão Gênica
Perfilação da Expressão Gênica/métodos
Técnicas de Inativação de Genes
Leishmania mexicana/enzimologia
Leishmania mexicana/crescimento & desenvolvimento
Leishmania mexicana/metabolismo
Macrófagos/parasitologia
Óxido Nítrico/metabolismo
Poliaminas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polyamines); 31C4KY9ESH (Nitric Oxide); 94ZLA3W45F (Arginine); EC 3.5.3.1 (Arginase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171119
[Lr] Data última revisão:
171119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171028
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0006026


  5 / 1547 MEDLINE  
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[PMID]:28798144
[Au] Autor:Hurrell BP; Beaumann M; Heyde S; Regli IB; Müller AJ; Tacchini-Cottier F
[Ad] Endereço:Department of Biochemistry, World Health Organization-Immunology Research and Training Collaborative Center, University of Lausanne, Epalinges, Switzerland; and.
[Ti] Título:Frontline Science: amastigotes can replicate within neutrophils.
[So] Source:J Leukoc Biol;102(5):1187-1198, 2017 Nov.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cutaneous leishmaniasis is a neglected tropical disease, causing a spectrum of clinical manifestations varying from self-healing to unhealing lesions that may be very difficult to treat. Emerging evidence points to a detrimental role for neutrophils during the first hours following infection with many distinct species (spp.) at a time when the parasite is in its nonreplicative promastigote form. Neutrophils have also been detected at later stages of infection in unhealing chronic cutaneous lesions. However, the interactions between these cells and the replicative intracellular amastigote form of the parasite have been poorly studied. Here, we show that amastigotes are efficiently internalized by neutrophils and that this process has only a low impact on neutrophil activation and apoptosis. In neutrophils, the amastigotes were found in acidified vesicles. Furthermore, within cutaneous unhealing lesions, heavily infected neutrophils were found with up to 6 parasites per cell. To investigate if the amastigotes could replicate within neutrophils, we generated photoconvertible fluorescent parasites. With the use of flow cytometry imaging and time-lapse microscopy, we could demonstrate that a subset of parasites replicated within neutrophils. Overall, our data reveal a novel role for neutrophils that can act as a niche for parasite replication during the chronic phase of infection, thereby contributing to disease pathology.
[Mh] Termos MeSH primário: Divisão Celular
Leishmania mexicana/crescimento & desenvolvimento
Leishmaniose Cutânea/parasitologia
Estágios do Ciclo de Vida/genética
Neutrófilos/parasitologia
Organismos Geneticamente Modificados/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Feminino
Citometria de Fluxo
Corantes Fluorescentes/metabolismo
Genes Reporter
Interações Hospedeiro-Parasita/imunologia
Leishmania mexicana/patogenicidade
Leishmania mexicana/ultraestrutura
Leishmaniose Cutânea/patologia
Camundongos
Camundongos Endogâmicos C57BL
Neutrófilos/ultraestrutura
Fagocitose
Processos Fotoquímicos
Imagem com Lapso de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.4HI0417-158R


  6 / 1547 MEDLINE  
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[PMID]:28703380
[Au] Autor:García M; Scull R; Satyal P; Setzer WN; Monzote L
[Ad] Endereço:Parasitology Department, Institute of Tropical Medicine "Pedro Kouri", Havana, Cuba.
[Ti] Título:Chemical Characterization, Antileishmanial Activity, and Cytotoxicity Effects of the Essential Oil from Leaves of Pluchea carolinensis (Jacq.) G. Don. (Asteraceae).
[So] Source:Phytother Res;31(9):1419-1426, 2017 Sep.
[Is] ISSN:1099-1573
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Current strategies to control leishmaniasis are mainly based on chemotherapy. However, none of the available drugs can be considered to be ideal to treat this disease. Because of the hydrophobic nature and bioactivities of their components, essential oils (EOs) can be considered as important sources for developing agents against intracellular pathogens, such as Leishmania parasites. In this study, we report the chemical characterization, antileishmanial activities, and cytotoxicity effect of the EO from Pluchea carolinensis (Jacq.) G. Don. (Asteraceae). Chemical analysis revealed that EO from aerial part from P. carolinensis is composed of 44 compounds. The main component was selin-11-en-4α-ol, which made up 51.0%. In vitro antileishmanial studies showed that P. carolinensis EO inhibited the growth of promastigotes (IC  = 24.7 ± 7.1 µg/mL) and amastigotes (IC  = 6.2 ± 0.1 µg/mL) of Leishmania amazonensis, while cytotoxicity evaluation revealed fivefold higher values than those for the parasites. In a model of experimental cutaneous leishmaniasis in BALB/c mice, five doses of EO at 30 mg/kg by intralesional route demonstrated smaller lesion size and parasite burden (p < 0.05) compared with animals treated with Glucantime® and untreated mice. In conclusion, in vitro and in vivo results showed the potentialities of EO from P. carolinensis with the future possibility of a new alternative in the treatment for leishmaniasis. Copyright © 2017 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Asteraceae/química
Leishmaniose Cutânea/tratamento farmacológico
Óleos Voláteis/farmacologia
[Mh] Termos MeSH secundário: Animais
Feminino
Leishmania/efeitos dos fármacos
Leishmania mexicana/efeitos dos fármacos
Meglumina/farmacologia
Camundongos
Camundongos Endogâmicos BALB C
Compostos Organometálicos/farmacologia
Folhas de Planta/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Oils, Volatile); 0 (Organometallic Compounds); 6HG8UB2MUY (Meglumine); 75G4TW236W (meglumine antimoniate)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1002/ptr.5869


  7 / 1547 MEDLINE  
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[PMID]:28622334
[Au] Autor:Mwenechanya R; Kovárová J; Dickens NJ; Mudaliar M; Herzyk P; Vincent IM; Weidt SK; Burgess KE; Burchmore RJS; Pountain AW; Smith TK; Creek DJ; Kim DH; Lepesheva GI; Barrett MP
[Ad] Endereço:Department of Biomedical Sciences, School of Veterinary Medicine, University of Zambia, Lusaka, Zambia.
[Ti] Título:Sterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana.
[So] Source:PLoS Negl Trop Dis;11(6):e0005649, 2017 Jun.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasites' genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14α-demethylase (CYP51). The mutation, N176I, is found outside of the enzyme's active site, consistent with the fact that the resistant line continues to produce the enzyme's product. Expression of wild-type sterol 14α-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself.
[Mh] Termos MeSH primário: Anfotericina B/farmacologia
Antiprotozoários/farmacologia
Resistência a Medicamentos
Leishmania mexicana/efeitos dos fármacos
Leishmania mexicana/enzimologia
Mutação de Sentido Incorreto
Esterol 14-Desmetilase/genética
[Mh] Termos MeSH secundário: Ergosterol/análise
Teste de Complementação Genética
Genoma de Protozoário
Leishmania mexicana/química
Metabolômica
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Polimorfismo de Nucleotídeo Único
Esterol 14-Desmetilase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Mutant Proteins); 7XU7A7DROE (Amphotericin B); EC 1.14.13.70 (Sterol 14-Demethylase); Z30RAY509F (Ergosterol)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0005649


  8 / 1547 MEDLINE  
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Alves, Ricardo J
Texto completo
[PMID]:28590516
[Au] Autor:Lavorato SN; Duarte MC; Lage DP; Tavares CAP; Coelho EAF; Alves RJ
[Ad] Endereço:Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
[Ti] Título:1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial agents.
[So] Source:Chem Biol Drug Des;90(5):981-986, 2017 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We describe herein the synthesis and antileishmanial activity of 1,3-bis(aryloxy)propan-2-ols. Five compounds (2, 3, 13, 17, and 18) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC  < 15.0 µm), and an influence of compound lipophilicity on activity was suggested. Most of the compounds were poorly selective, as they showed toxicity toward murine macrophages, except 17 and 18, which presented good selective indexes (SI ≥ 10.0). The five more active compounds (2, 3, 13, 17, and 18) were selected for the treatment of infected macrophages, and all of them were able to reduce the number of internalized parasites by more than 80%, as well as the number of infected macrophages by more than 70% in at least one of the tested concentrations. Altogether, these results demonstrate the potential of these compounds as new hits of antileishmanial agents and open future possibilities for them to be tested in in vivo studies.
[Mh] Termos MeSH primário: Leishmania mexicana/efeitos dos fármacos
Leishmaniose Cutânea/tratamento farmacológico
Propanóis/química
Propanóis/uso terapêutico
Tripanossomicidas/química
Tripanossomicidas/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Concentração Inibidora 50
Leishmaniose Cutânea/parasitologia
Macrófagos/parasitologia
Camundongos Endogâmicos BALB C
Propanóis/farmacologia
Tripanossomicidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Propanols); 0 (Trypanocidal Agents)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170608
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.13024


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[PMID]:28573235
[Au] Autor:Nieto-Yañez OJ; Resendiz-Albor AA; Ruiz-Hurtado PA; Rivera-Yañez N; Rodriguez-Canales M; Rodriguez-Sosa M; Juarez-Avelar I; Rodriguez-Lopez MG; Canales-Martinez MM; Rodriguez-Monroy MA
[Ad] Endereço:Laboratorio de Inmunidad de Mucosas. Sección de Estudios de Posgrado e Investigación. Escuela Superior de Medicina, del Instituto Politécnico Nacional. Av. Plan de San Luis S/N, Colonia Casco de Santo Tomas, Miguel Hidalgo, CP. 11350. Ciudad de México, D.F.
[Ti] Título: AND ANTILEISHMANIAL EFFECTS OF METHANOLIC EXTRACT FROM BARK OF APTERA.
[So] Source:Afr J Tradit Complement Altern Med;14(2):188-197, 2017.
[Is] ISSN:2505-0044
[Cp] País de publicação:Nigeria
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cutaneous leishmaniasis lacks effective and well-tolerated treatments. The current therapies mainly rely on antimonial drugs that are inadequate because of their poor efficacy. Traditional medicine offers a complementary alternative for the treatment of various diseases. Additionally, several plants have shown success as anti-leishmanial agents. Therefore, we sought to evaluate the and activity of MEBA against . MATERIALS AND METHODS: Methanolic extract of was obtained by macetration, after we determined anti-leishmanial activity of MEBA by MTT assay and the induced apoptosis in promastigotes by flow cytometry. To analyze the anti-leishmanial activity, we used infected mice that were treated and not treated with MEBA and we determined the levels of cytokines using ELISA. The phytochemical properties were determined by CG-MS and DPPH assay. RESULTS: We determined of LC of 0.408 mg/mL of MEBA for anti-leishmanial activity. MEBA induced apoptosis in promastigotes (15.3% ± 0.86). Treated mice exhibited smaller lesions and contained significantly fewer parasites than did untreated mice; in addition, we found that IFN-γ and TNF-α increased in the sera of MEBA-treated mice. GC-MS analysis showed that podophyllotoxin was the most abundant compound. Evaluation of the activity by DPPH assay demonstrated an SC of 11.72 µg/mL. CONCLUSION: Based on the above data, it was concluded that MEBA is a good candidate in the search for new anti-leishmanial agents.
[Mh] Termos MeSH primário: Bursera/química
Leishmania mexicana
Leishmaniose Cutânea/tratamento farmacológico
Fitoterapia
Extratos Vegetais/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Feminino
Interferon gama/sangue
Leishmaniose Cutânea/sangue
Leishmaniose Cutânea/parasitologia
Medicina Tradicional
Camundongos Endogâmicos BALB C
Casca de Planta
Extratos Vegetais/farmacologia
Podofilotoxina/análise
Podofilotoxina/farmacologia
Podofilotoxina/uso terapêutico
Fator de Necrose Tumoral alfa/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plant Extracts); 0 (Tumor Necrosis Factor-alpha); 82115-62-6 (Interferon-gamma); L36H50F353 (Podophyllotoxin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE
[do] DOI:10.21010/ajtcam.v14i2.20


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[PMID]:28571825
[Au] Autor:Alzahrani KJ; Matyugina ES; Khandazhinskaya AL; Kochetkov SN; Seley-Radtke KL; Koning HP
[Ad] Endereço:Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK; Department of Clinical Laboratory, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
[Ti] Título:Evaluation of the antiprotozoan properties of 5'-norcarbocyclic pyrimidine nucleosides.
[So] Source:Bioorg Med Chem Lett;27(14):3081-3086, 2017 07 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5'-nor variants. Here, we report the result of our preliminary screening of a series of 5'-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4',N -di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti-leishmanial activities indicates that this mechanism is likely shared between the two species. EC values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross-resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration.
[Mh] Termos MeSH primário: Antiprotozoários/química
Nucleosídeos de Pirimidina/química
[Mh] Termos MeSH secundário: Antiprotozoários/farmacologia
Resistência a Medicamentos/efeitos dos fármacos
Fluoruracila/farmacologia
Leishmania mexicana/efeitos dos fármacos
Nucleosídeos de Pirimidina/farmacologia
Relação Estrutura-Atividade
Trypanosoma brucei brucei/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Pyrimidine Nucleosides); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170603
[St] Status:MEDLINE



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