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1.
AAPS PharmSciTech ; 21(1): 9, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797083

RESUMO

Increased human-pet interactions have led to concerns related to the prevention and treatment of ectoparasite infestations. Fipronil (FIP) is a widely used ectoparasiticide in veterinary medicine available for topical administration; however, its use may cause damage to the owners and the environment. The aim of the study was to develop immediate-release tablets of FIP, as well as to determine its pharmacokinetic properties after oral administration in beagle dogs. The prepared FIP tablets were evaluated for pre-compression (angle of repose, speed flow, and Carr's index) and post-compression (weight variation, friability, thickness, hardness, disintegration time, and dissolution rate) parameters. Orally administered FIP at a dose of 2 mg/kg was rapidly absorbed with Cmáx of 3.13 ± 1.39 µg/mL at 1.83 ± 0.40 h post treatment (P.T.) and metabolized with 1.27 ± 1.04 µg/mL at 2.33 ± 0.82 h P.T. for fipronil sulfone (SULF) (the primary metabolite). The elimination of FIP and SULF occurred slowly and had maintained quantifiable plasma levels in the blood for up to 28 days P.T. The goal of the study is aligned with the concept of One Health, which aims to collaboratively achieve the best health for people, animals, and the environment. Therefore, the use of FIP tablets for the control of ectoparasites in dogs may be a safer alternative for owners and the environment.


Assuntos
Antiparasitários/química , Antiparasitários/farmacocinética , Pirazóis/química , Pirazóis/farmacocinética , Administração Oral , Animais , Antiparasitários/administração & dosagem , Cães , Dureza , Pirazóis/administração & dosagem , Comprimidos , Poluição da Água/prevenção & controle
2.
Ecotoxicol Environ Saf ; 183: 109489, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31394379

RESUMO

Avermectins and moxidectin are antiparasitics widely used as active pharmaceutical ingredients in veterinary medicine, as well as in pesticide formulations for pest control in agriculture. Although the use of these compounds provides benefits to agribusiness, they can impact the environment, since a large part of these substances may reach the soil and water from the excreta of treated animals and following direct applications to crops. The present work had the objective of evaluating the dissipation behaviors of abamectin, doramectin, eprinomectin, ivermectin, and moxidectin in four native Brazilian soils of different textural classes (clay, sandy-clay, sandy, and sandy-clay-loam), following OECD Guideline 307. The studies were conducted in a climate chamber at 22 °C, 71% relative humidity, and protected from light. The dissipation studies were carried out with all drugs together, since no difference was verified when studies were done with each drug separately. The concentrations of the drugs in the soils were determined using an ultra-high performance liquid chromatograph coupled to a fluorescence detector or a tandem mass spectrometer. The dissipation half-life (DT50) values ranged from 9 to 16 days and the calculated GUS index values were in the range from -1.10 to 0.08, indicating low mobility of the drugs in the soils evaluated and low tendency for leaching. In addition, a field study was carried out to evaluate the dissipation of abamectin after application of a foliar pesticide in an orange crop. A DT50 of 9 days was determined, which was similar to that obtained under controlled conditions in the climate chamber (12 days), indicating that biotransformation was the primary process influencing the overall dissipation.


Assuntos
Antiparasitários/química , Ivermectina/análogos & derivados , Macrolídeos/metabolismo , Praguicidas/química , Poluentes do Solo/química , Solo/química , Antiparasitários/análise , Brasil , Monitoramento Ambiental , Meia-Vida , Ivermectina/análise , Ivermectina/química , Ivermectina/metabolismo , Macrolídeos/análise , Macrolídeos/química , Praguicidas/análise , Poluentes do Solo/análise
3.
Molecules ; 24(15)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374887

RESUMO

Dithiocarbamates represent a class of compounds that were evaluated in different biomedical applications because of their chemical versatility. For this reason, several pharmacological activities have already been attributed to these compounds, such as antiparasitic, antiviral, antifungal activities, among others. Therefore, compounds that are based on dithiocarbamates have been evaluated in different in vivo and in vitro models as potential new antimicrobials. Thus, the purpose of this review is to present the possibilities of using dithiocarbamate compounds as potential new antitrypanosomatids-drugs, which could be used for the pharmacological control of Chagas disease, leishmaniasis, and African trypanosomiasis.


Assuntos
Antiparasitários/uso terapêutico , Leishmaniose/tratamento farmacológico , Tiocarbamatos/uso terapêutico , Trypanosoma/efeitos dos fármacos , Animais , Antiparasitários/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Humanos , Leishmaniose/parasitologia , Tiocarbamatos/química , Trypanosoma/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
4.
Curr Top Med Chem ; 19(22): 2041-2048, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31340737

RESUMO

BACKGROUND: Functional and structural diversity of proteins of snake venoms is coupled with a wide repertoire of pharmacological effects. Snake venoms are targets of studies linked to searching molecules with biotechnological potential. METHODS: A homologue phospholipase A2 (BmatTX-IV) was obtained using two chromatographic techniques. Mass spectrometry and two-dimensional gel electrophoresis were used to determine the molecular mass and isoelectric point, respectively. By means of Edman degradation chemistry, it was possible to obtain the partial sequence of amino acids that comprise the isolated toxin. Trypanocidal, leishmanicidal and cytoxic activity against Trypanosoma cruzi, Leishmania infantum and murine fibrobasts was determinated. RESULTS: Combination of both chromatographic steps used in this study demonstrated efficacy to obtain the PLA2-Lys49. BmatTX-IV showed molecular mass and isoelectric point of 13.55 kDa and 9.3, respectively. Amino acid sequence of N-terminal region (51 residues) shows the presence of Lys49 residue at position 49, a distinctive trait of enzymatically inactive PLA2. Bothrops mattogrossensis snake venom showed IC50 values of 11.9 µg/mL against Leishmania infantum promastigotes and of 13.8 µg/mL against Trypanosoma cruzi epimastigotes, respectively. On the other hand, the venom showed a high cytotoxic activity (IC50 value of 16.7 µg/mL) against murine fibroblasts, whereas the BmatTX-IV showed IC50 value of 81.2 µg/mL. CONCLUSION: Physicochemical and biological characterization of snake venoms components is critically important, since these complex mixtures provide a source of molecules with antiparasitic potential, making further studies necessary to identify and characterize components with higher efficacy and selectivity.


Assuntos
Antiparasitários/farmacologia , Leishmania infantum/efeitos dos fármacos , Fosfolipases A2/farmacologia , Venenos de Serpentes/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/química , Antiparasitários/isolamento & purificação , Bothrops , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Camundongos , Paraguai , Testes de Sensibilidade Parasitária , Fosfolipases A2/química , Fosfolipases A2/isolamento & purificação , Venenos de Serpentes/química , Venenos de Serpentes/isolamento & purificação , Relação Estrutura-Atividade
5.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216674

RESUMO

We previously synthesized an hydroxamate derivative (N-hydroxy-4-[2-(3- methoxyphenyl)acetamido]benzamide) named 363 with potent anti-Toxoplasma gondii activity and histone deacetylase inhibitor (HDACi) effects. Here we show that 1-N-hydroxy-4-N- [(2-methoxyphenyl)methyl]benzene-1,4-dicarboxamide, a 363 isomer, does not have antiparasitic potency and has a 13-fold decrease in HDACi activity. The in silico modeling of T. gondii HDACs of the type II strain discloses identity varying from 25% to 62% on more than 250 residues for S8EP32_TOXG and A0A125YPH4_TOXGM. We observed a high conservation degree with the human HDAC2 (53% and 64% identity, respectively) and a moderate one with the human HDAC8 (30-40%). Two other TgHDACs, S8F6L4_TOXGM and S8GEI3_TOXGM, were identified as displaying a higher similarity with some bacterial orthologs (~35%) than with the human enzymes (~25%). The docking in parallel of the two compounds on the models generated allowed us to gain insights on the docking of these hydroxamate derivatives that guide their specificity and potency against T. gondii histone deacetylase. This information would constitute the rationale from which more specific derivatives can be synthetized.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Histona Desacetilases/química , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ligação Proteica , Relação Estrutura-Atividade , Toxoplasma/efeitos dos fármacos
6.
Mar Drugs ; 17(5)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035452

RESUMO

Rare actinomycetes are prolific in the marine environment; however, knowledge about their diversity, distribution and biochemistry is limited. Marine rare actinomycetes represent a rather untapped source of chemically diverse secondary metabolites and novel bioactive compounds. In this review, we aim to summarize the present knowledge on the isolation, diversity, distribution and natural product discovery of marine rare actinomycetes reported from mid-2013 to 2017. A total of 97 new species, representing 9 novel genera and belonging to 27 families of marine rare actinomycetes have been reported, with the highest numbers of novel isolates from the families Pseudonocardiaceae, Demequinaceae, Micromonosporaceae and Nocardioidaceae. Additionally, this study reviewed 167 new bioactive compounds produced by 58 different rare actinomycete species representing 24 genera. Most of the compounds produced by the marine rare actinomycetes present antibacterial, antifungal, antiparasitic, anticancer or antimalarial activities. The highest numbers of natural products were derived from the genera Nocardiopsis, Micromonospora, Salinispora and Pseudonocardia. Members of the genus Micromonospora were revealed to be the richest source of chemically diverse and unique bioactive natural products.


Assuntos
Actinobacteria/química , Organismos Aquáticos/química , Produtos Biológicos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antiparasitários/química , Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação
7.
Parasite ; 26: 26, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31041897

RESUMO

Six benzoylphenyl ureas are currently used in formulations approved as veterinary medicines: diflubenzuron for fly control mainly on cattle, lice and blowfly strike control on sheep, and lice control on farmed salmonids; lufenuron for flea control on dogs and cats and for lice control on farmed salmonids; triflumuron for lice and blowfly strike control on sheep; fluazuron for tick control on cattle; teflubenzuron for lice control on farmed salmon; and novaluron for fly and tick control on cattle and for flea control on dogs. Resistance to diflubenzuron and triflumuron has already been reported for sheep body lice and blowflies, and to fluazuron in cattle ticks. These and other minor veterinary usages, as well as the current status of resistance, are reviewed and perspectives for future opportunities are discussed based on unexplored potentials and threats posed by future resistance development.


Assuntos
Antiparasitários/uso terapêutico , Resistência a Medicamentos , Doenças Parasitárias em Animais/tratamento farmacológico , Drogas Veterinárias/uso terapêutico , Animais , Antiparasitários/química , Benzamidas/uso terapêutico , Diflubenzuron/uso terapêutico , Drogas Veterinárias/química
8.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022871

RESUMO

Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against a wide panel of bacteria, fungi and parasitic protozoa. Forty-five compounds were identified in the studied EO, of which lavandulyl acetate (40.1%) and thymyl isobutyrate (13.9%) were the major components. The EO did not inhibit bacterial or fungal growth at the maximum concentration tested (64 µg/mL), although it displayed activity on all evaluated protozoa (IC50 values ranging from 2.2 to 56.6 µg/mL). In parallel, the EO demonstrated a noteworthy cytotoxic activity against peritoneal macrophages (CC50 values of 28.0 µg/mL). The most sensitive microorganism was Trypanosoma cruzi, which had a superior activity (IC50 = 2.2 µg/mL) and selectivity (SI = 13) in respect to other parasitic protozoa and the reference drug (p < 0.05). Further in vivo studies are needed to evaluate the potential use of this EO and the main compounds as antitrypanosomal agents. To our knowledge, this is the first report of chemical characterization and antimicrobial assessment of the EO from P. matricarioides.


Assuntos
Asteraceae/química , Proliferação de Células/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Óleos Voláteis/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antiparasitários/química , Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Fungos/efeitos dos fármacos , Fungos/patogenicidade , Humanos , Testes de Sensibilidade Microbiana , Óleos Voláteis/isolamento & purificação , Óleos Voláteis/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade
9.
PLoS One ; 14(4): e0214193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939131

RESUMO

Cocos nucifera (C. nucifera) (the coconut palm tree) has been traditionally used to fight a number of human diseases, but only a few studies have tested its components against parasites such as those that cause malaria. In this study, C. nucifera samples were collected from a private natural reserve in Punta Patiño, Darien, Panama. The husk, leaves, pulp, and milk of C. nucifera were extracted and evaluated against the parasites that cause Chagas' disease or American trypanosomiasis (Trypanosoma cruzi), leishmaniasis (Leishmania donovani) and malaria (Plasmodium falciparum), as well as against a line of breast cancer cells. While there was no activity in the rest of the tests, five and fifteen-minute aqueous decoctions of leaves showed antiplasmodial activity at 10% v/v concentration. Removal of some HPLC fractions resulted in loss of activity, pointing to the presence of synergy between the components of the decoction. Chemical molecules were separated and identified using an ultra-performance liquid chromatography (UPLC) approach coupled to tandem mass spectrometry (LC-MS/MS) using atmospheric pressure chemical ionization quadrupole-time of flight mass spectrometry (APCI-Q-TOF-MS) and molecular networking analysis, revealing the presence of compounds including polyphenol, flavone, sterol, fatty acid and chlorophyll families, among others.


Assuntos
Antiparasitários/farmacologia , Cocos/química , Leishmaniose/tratamento farmacológico , Malária Falciparum/tratamento farmacológico , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antiparasitários/química , Arecaceae/química , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Leishmaniose/parasitologia , Malária Falciparum/parasitologia , Panamá , Folhas de Planta/química , Espectrometria de Massas em Tandem , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/patogenicidade
10.
Molecules ; 24(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959737

RESUMO

Guanine-quadruplex (G4) motifs, at both the DNA and RNA levels, have assumed an important place in our understanding of the biology of eukaryotes, bacteria and viruses. However, it is generally little known that their very first description, as well as the foundational work on G4s, was performed on protozoans: unicellular life forms that are often parasitic. In this review, we provide a historical perspective on the discovery of G4s, intertwined with their biological significance across the protozoan kingdom. This is a history in three parts: first, a period of discovery including the first characterisation of a G4 motif at the DNA level in ciliates (environmental protozoa); second, a period less dense in publications concerning protozoa, during which DNA G4s were discovered in both humans and viruses; and third, a period of renewed interest in protozoa, including more mechanistic work in ciliates but also in pathogenic protozoa. This last period has opened an exciting prospect of finding new anti-parasitic drugs to interfere with parasite biology, thus adding new compounds to the therapeutic arsenal.


Assuntos
DNA de Protozoário/genética , Eucariotos/genética , Quadruplex G , Doenças Parasitárias/genética , Animais , Antiparasitários/química , Antiparasitários/uso terapêutico , Eucariotos/efeitos dos fármacos , Humanos , Parasitos/genética , Doenças Parasitárias/tratamento farmacológico , Doenças Parasitárias/parasitologia , RNA/genética , Vírus/genética
11.
Molecules ; 24(7)2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959974

RESUMO

Piper species are aromatic plants used as spices in the kitchen, but their secondary metabolites have also shown biological effects on human health. These plants are rich in essential oils, which can be found in their fruits, seeds, leaves, branches, roots and stems. Some Piper species have simple chemical profiles, while others, such as Piper nigrum, Piper betle, and Piper auritum, contain very diverse suites of secondary metabolites. In traditional medicine, Piper species have been used worldwide to treat several diseases such as urological problems, skin, liver and stomach ailments, for wound healing, and as antipyretic and anti-inflammatory agents. In addition, Piper species could be used as natural antioxidants and antimicrobial agents in food preservation. The phytochemicals and essential oils of Piper species have shown strong antioxidant activity, in comparison with synthetic antioxidants, and demonstrated antibacterial and antifungal activities against human pathogens. Moreover, Piper species possess therapeutic and preventive potential against several chronic disorders. Among the functional properties of Piper plants/extracts/active components the antiproliferative, anti-inflammatory, and neuropharmacological activities of the extracts and extract-derived bioactive constituents are thought to be key effects for the protection against chronic conditions, based on preclinical in vitro and in vivo studies, besides clinical studies. Habitats and cultivation of Piper species are also covered in this review. In this current work, available literature of chemical constituents of the essential oils Piper plants, their use in traditional medicine, their applications as a food preservative, their antiparasitic activities and other important biological activities are reviewed.


Assuntos
Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Piper/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Ecossistema , Conservação de Alimentos , Medicina Tradicional , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Piper/classificação , Extratos Vegetais/química , Extratos Vegetais/farmacologia
12.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925657

RESUMO

Sesquiterpene lactones are naturally occurring compounds mainly found in the Asteraceae family. These types of plant metabolites display a wide range of biological activities, including antiprotozoal activity and are considered interesting structures for drug discovery. Four derivatives were synthesized from estafietin (1), isolated from Stevia alpina (Asteraceae): 11ßH,13-dihydroestafietin (2), epoxyestafietin (3a and 3b), 11ßH,13-methoxyestafietin, (4) and 11ßH,13-cianoestafietin. The antiprotozoal activity against Trypanosoma cruzi and Leishmania braziliensis of these compounds was evaluated. Epoxyestafietin was the most active compound against T. cruzi trypomastigotes and amastigotes (IC50 values of 18.7 and 2.0 µg/mL, respectively). Estafietin (1) and 11ßH,13-dihydroestafietin (2) were the most active and selective compounds on L. braziliensis promastigotes (IC50 values of 1.0 and 1.3 µg/mL, respectively). The antiparasitic activity demonstrated by estafietin and some of its derivatives make them promising candidates for the development of effective compounds for the treatment of Chagas disease and leihsmaniasis.


Assuntos
Leishmania braziliensis/efeitos dos fármacos , Sesquiterpenos de Guaiano/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/química , Antiparasitários/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Morte Celular/efeitos dos fármacos , Espectroscopia de Prótons por Ressonância Magnética , Sesquiterpenos de Guaiano/química , Trypanosoma cruzi/crescimento & desenvolvimento , Células Vero
13.
Met Ions Life Sci ; 192019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30855114

RESUMO

Metal compounds seem to be a promising approach in the search of new therapeutic solutions for neglected tropical diseases. In this chapter, efforts in the design of prospective metal-based drugs for the treatment of Chagas disease, human African trypanosomiasis, and leishmaniasis are discussed. Careful selection of the metal center (including organometallic cores) and the types and number of coordinated ligands is essential for controlling the reactivity of the complexes and hence, tuning their biological properties. In a target-based approach, some targets that have been validated for organic antiparasitic compounds are expected to remain targets for metal complexes of these compounds. In addition, specific targets for metal compounds, like parasitic enzymes or DNA, would also be included for these metal complexes leading to potential additive or even synergistic effects between organic ligand and metal ion. However, even though a good number of prospective antiparasitic metal-based drugs have been developed, further systematic efforts are needed for these metal compounds to accomplish the regulatory guidelines that let them reach the different stages of clinical trials.


Assuntos
Antiparasitários/química , Metais/química , Doença de Chagas/tratamento farmacológico , Humanos , Leishmaniose/tratamento farmacológico , Estudos Prospectivos , Tripanossomíase Africana/tratamento farmacológico
14.
Molecules ; 24(3)2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30744161

RESUMO

One of the key stages in the development of new therapies in the treatment of toxoplasmosis is the identification of new non-toxic small molecules with high specificity to Toxoplasma gondii. In the search for such structures, thiosemicarbazide-based compounds have emerged as a novel and promising leads. Here, a series of imidazole-thiosemicarbazides with suitable properties for CNS penetration was evaluated to determine the structural requirements needed for potent anti-Toxoplasma gondii activity. The best 4-arylthiosemicarbazides 3 and 4 showed much higher potency when compared to sulfadiazine at concentrations that are non-toxic to the host cells, indicating a high selectivity of their anti-toxoplasma activity.


Assuntos
Antiparasitários/farmacologia , Avaliação Pré-Clínica de Medicamentos , Semicarbazidas/farmacologia , Toxoplasma/efeitos dos fármacos , Animais , Antiparasitários/química , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Semicarbazidas/química , Relação Estrutura-Atividade , Toxoplasmose/tratamento farmacológico , Toxoplasmose/parasitologia
15.
Bioorg Med Chem ; 27(7): 1350-1361, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30808607

RESUMO

As a continuation of our project aimed at searching for new chemotherapeutic agents against American trypanosomiasis (Chagas disease), new selenocyanate derivatives were designed, synthesized and biologically evaluated against the clinically more relevant dividing form of Trypanosoma cruzi, the etiologic agent of this illness. In addition, in order to establish the role of each part of the selenocyanate moiety, different derivatives, in which the selenium atom or the cyano group were absent, were conceived, synthesized and biologically evaluated. In addition, in order to study the optimal position of the terminal phenoxy group, new regioisomers of WC-9 were synthesized and evaluated against T. cruzi. Finally, the resolution of a racemic mixture of a very potent conformationally rigid analogue of WC-9 was accomplished and further tested as growth inhibitors of T. cruzi proliferation. The results provide further insight into the role of the selenocyanate group in its antiparasitic activity.


Assuntos
Antiparasitários/farmacologia , Compostos Organosselênicos/farmacologia , Éteres Fenílicos/farmacologia , Tiocianatos/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiparasitários/síntese química , Antiparasitários/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Testes de Sensibilidade Parasitária , Éteres Fenílicos/química , Relação Estrutura-Atividade , Tiocianatos/química , Células Vero
16.
Arch Biochem Biophys ; 664: 24-39, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30707942

RESUMO

Parasites are scarcely addressed target for antimicrobial peptides despite their big impact in health and global economy. The notion of antimicrobial peptides is frequently associated to the innate immune defense of vertebrates and invertebrate vectors, as the ultimate recipients of the parasite infection. These antiparasite peptides are produced by ribosomal synthesis, with few post-translational modifications, and their diversity come mostly from their amino acid sequence. For many of them permeabilization of the cell membrane of the targeted pathogen is crucial for their microbicidal mechanism. In contrast, cyanobacterial peptides are produced either by ribosomal or non-ribosomal biosynthesis. Quite often, they undergo heavy modifications, such as the inclusion of non-proteinogenic amino acids, lipid acylation, cyclation, Nα-methylation, or heterocyclic rings. Furthermore, the few targets identified for cyanobacterial peptides in parasites are intracellular. Some cyanobacterial antiparasite peptides are active at picomolar concentrations, whereas those from higher eukaryotes usually work in the micromolar range. In all, cyanobacterial peptides are an appealing target to develop new antiparasite therapies and a challenge in the invention of new synthetic methods for peptides. This review aims to provide an updated appraisal of antiparasite cyanobacterial peptides and to establish a side-by -side comparison with those antiparasite peptides from higher eukaryotes.


Assuntos
Antiparasitários/farmacologia , Cianobactérias/química , Peptídeos/farmacologia , Antiparasitários/química , Peptídeos/química
17.
J Biol Chem ; 294(14): 5365-5385, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670594

RESUMO

Aminoacyl-tRNA synthetases (ARSs) are universal enzymes that catalyze the attachment of amino acids to the 3' ends of their cognate tRNAs. The resulting aminoacylated tRNAs are escorted to the ribosome where they enter protein synthesis. By specifically matching amino acids to defined anticodon sequences in tRNAs, ARSs are essential to the physical interpretation of the genetic code. In addition to their canonical role in protein synthesis, ARSs are also involved in RNA splicing, transcriptional regulation, translation, and other aspects of cellular homeostasis. Likewise, aminoacylated tRNAs serve as amino acid donors for biosynthetic processes distinct from protein synthesis, including lipid modification and antibiotic biosynthesis. Thanks to the wealth of details on ARS structures and functions and the growing appreciation of their additional roles regulating cellular homeostasis, opportunities for the development of clinically useful ARS inhibitors are emerging to manage microbial and parasite infections. Exploitation of these opportunities has been stimulated by the discovery of new inhibitor frameworks, the use of semi-synthetic approaches combining chemistry and genome engineering, and more powerful techniques for identifying leads from the screening of large chemical libraries. Here, we review the inhibition of ARSs by small molecules, including the various families of natural products, as well as inhibitors developed by either rational design or high-throughput screening as antibiotics and anti-parasitic therapeutics.


Assuntos
Aminoacil-tRNA Sintetases , Antibacterianos , Antiparasitários , Inibidores Enzimáticos , Doenças Parasitárias , Aminoacil-tRNA Sintetases/antagonistas & inibidores , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Antiparasitários/química , Antiparasitários/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , /enzimologia , /patologia , Doenças Parasitárias/tratamento farmacológico , Doenças Parasitárias/enzimologia , Doenças Parasitárias/genética , Processamento de RNA/efeitos dos fármacos , RNA de Transferência/genética , RNA de Transferência/metabolismo
18.
Eur J Med Chem ; 166: 32-47, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30684869

RESUMO

Despite some progress in recent years, the fight against parasitic diseases still remains a great challenge. Parasitic diseases affect primarily (but not exclusively) the poorest people living in underdeveloped regions of the world. The distribution of parasitoses are linked to tropical and subtropical climate conditions, to population growth and to impoverishment. If not treated, parasitic diseases may lead to serious health problems, and even death. Particularly vulnerable groups include infants and young children, pregnant women and immunocompromised individuals. Polyether ionophore antibiotics (ionophores), traditionally used in veterinary medicine as anti-coccidial feed additives and non-hormonal growth promoters, are of considerable interest, as they have been found to be highly effective agents against various parasites, both in vitro and in vivo. This review summarizes the anti-parasitic effects of the most important polyether ionophores against parasites that are responsible for a number of animal and human parasitic diseases. Recent findings and advances that support the potential of polyether ionophore antibiotics as novel anti-parasitic drug candidates are also presented and discussed.


Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Éteres/química , Éteres/farmacologia , Ionóforos/química , Ionóforos/farmacologia , Parasitos/efeitos dos fármacos , Animais , Humanos
19.
J Asian Nat Prod Res ; 21(7): 679-687, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29733224

RESUMO

Inspired from the leishmanicidal and antibacterial potential of the fractions obtained from the crude extract of Olea ferruginea stem, the anti-leishmanial ethyl acetate fraction was subjected to chromatographic separation, leading to the isolation of a new compound ferruginan (1) and a known compound (+)- cycloolivil (2). The structures of 1 and 2 were determined by various spectroscopic techniques and were assayed for their in vitro antibacterial and leishmanicidal potential. Compound 1 showed 75% inhibition after 24 h of incubation and 98% inhibition after 48 h of incubation against Leishmania tropica KWH23 promastigotes at 100 µg/mL concentration, while compound 2 exhibited 73% and 96% inhibition at the same concentration and incubation time. Compound 1 also showed good activity against various bacterial pathogens.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Leishmania tropica/efeitos dos fármacos , Olea/química , Animais , Bactérias/efeitos dos fármacos , Lignanas/química , Lignanas/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Folhas de Planta/química
20.
Nat Prod Res ; 33(24): 3465-3471, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29863902

RESUMO

Leishmania infantum is responsible for the cutaneous and visceral form of this zoonotic disease, which is potentially lethal for humans and has dogs as natural reservoir. In the light of the antiparasitic properties displayed by several natural products, L. infantum promastigotes were exposed to green tea (Camellia sinensis) leaves extract (GTE) and pomegranate (Punica granatum) peel extract (PPE). Both extracts, characterized by NMR and HPLC analysis, inhibited parasite proliferation in a dose-dependent manner, as proved by IC50 evaluation determined by MTT assay.Moreover, the reversibility assay showed that GTE and PPE have an aptotosis-mediated leishmanicidal effect, as evidenced by DNA degradation and confirmed by DNA fragmentation and real-time PCR analyses. Finally, for the first time morphological and ultrastructural alterations induced by a P. granatum extract on Leishmania were shown by the use of light, transmission and scanning electron microscopy.


Assuntos
Antiparasitários/farmacologia , Camellia sinensis/química , Leishmania infantum/efeitos dos fármacos , Extratos Vegetais/farmacologia , /química , Antiparasitários/administração & dosagem , Antiparasitários/química , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Cromatografia Líquida de Alta Pressão , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Frutas/química , Leishmania infantum/genética , Leishmania infantum/ultraestrutura , Espectroscopia de Ressonância Magnética , Extratos Vegetais/química , Folhas de Planta/química
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