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1.
Eur J Pharmacol ; 891: 173748, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33227285

RESUMO

The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazoxanide which is reported to exert broad-spectrum antiviral activity against various viral infections, revealed good in vitro activity against SARS-CoV-2 in cell culture assays, suggesting potential for repurposing in COVID-19. Furthermore, nitazoxanide displays the potential to boost host innate immune responses and thereby tackle the life-threatening cytokine storm. Possibilities of improving lung, as well as multiple organ damage and providing value addition to COVID-19 patients with comorbidities, are other important facets of the drug. The review juxtaposes the role of nitazoxanide in fighting COVID-19 pathogenesis at multiple levels highlighting the great promise the drug exhibits. The in silico data and in vitro efficacy in cell lines confirms the promise of nitazoxanide. Several approved clinical trials world over further substantiate leveraging nitazoxanide for COVID-19 therapy.


Assuntos
Reposicionamento de Medicamentos , Tiazóis/farmacologia , Antiprotozoários/farmacologia , /imunologia , Ensaios Clínicos como Assunto , Humanos , Imunidade Inata/efeitos dos fármacos , /fisiologia
2.
Exp Parasitol ; 220: 108033, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33166530

RESUMO

Infection with Leishmania infantum causes the disease visceral leishmaniasis (VL), which is a serious clinical and veterinary problem. The drugs used to treat canine leishmaniasis (CanL) do not cause complete parasite clearance; they can be toxic, and emerging drug resistance in parasite populations limits their clinical utility. Therefore, in this study we have evaluated the toxicity and efficacy of joint treatment with a 1:1 mixture of sodium stibogluconate-NIV (SSG-NIV, 10 mg Sbv/day) and paromomycin-NIV (PMM-NIV, 10 mg PMM/kg/day), given intravenously daily for seven days from day 270 post-infection, to nine-month-old female beagle dogs (n = 6) experimentally infected with Leishmania infantum. Treatment significantly improved the clinical symptoms of VL infection in all the treated dogs, reduced parasite burdens in lymph nodes and bone marrow, and all symptomatic treated dogs, were asymptomatic at 90 days post-treatment. Treatment was associated with a progressive and significant decrease in specific IgG anti-Leishmania antibodies using parasite soluble antigen (p < 0.01) or rK39 (p < 0.01) as the target antigen. In addition, all dogs were classified as parasite negative based on Leishmania nested PCR and quantitative real time PCR tests and as well as an inability to culture of promastigote parasites from lymph nodes and bone marrow tissue samples taken at day 90 post-treatment. However, treatment did not cure the dogs as parasites were detected at 10 months post-treatment, indicating that a different dosing regimen is required to cause long term cure or prevent relapse.


Assuntos
Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania donovani/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Paromomicina/uso terapêutico , Administração Intravenosa , Análise de Variância , Animais , Gluconato de Antimônio e Sódio/administração & dosagem , Gluconato de Antimônio e Sódio/farmacologia , Antiprotozoários/administração & dosagem , Antiprotozoários/farmacologia , Contagem de Células Sanguíneas , Análise Química do Sangue , Medula Óssea/parasitologia , Cricetinae , Reservatórios de Doenças , Cães , Feminino , Leishmania donovani/imunologia , Leishmania donovani/isolamento & purificação , Leishmania infantum/imunologia , Leishmania infantum/isolamento & purificação , Fígado/parasitologia , Linfonodos/parasitologia , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos BALB C , Paromomicina/administração & dosagem , Paromomicina/farmacologia , Pele/parasitologia , Baço/parasitologia
3.
An Acad Bras Cienc ; 92(4): e20201181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33295583

RESUMO

Leishmaniasis is caused by protozoan parasites belonging to the genus Leishmania and includes cutaneous, mucocutaneous and visceral clinical forms. Drugs currently available for leishmaniasis treatment present high toxicity, and development of parasite resistance. Plants constitute an important source of compounds with leishmanicidal potential. This study aimed to evaluate the anti-Leishmania amazonensis activity of the terpenoid fraction of Eugenia pruniformis leaves (TF-EpL). TF-EpL was active against the promastigote and intracellular amastigote forms of L. amazonensis with IC50(24h) value of 43.60µg/mL and 44.77µg/mL, respectively. TF-EpL altered the cell cycle of the parasite, increasing 2.32-fold the cells in the Sub-G0/G1 phase. TF-EpL also changed the ΔΨm and increased ROS and the number of annexin-V-PI positive promastigotes, which suggests incidental death. ß-sitosterol, ursolic acid, corosolic acid and asiatic acid were isolated from TF-EpL. The results showed the antileishmanial activity of E. pruniformis terpenoids and its potential for further studies as a source of new drugs for leishmaniasis.


Assuntos
Antiprotozoários , Eugenia , Leishmania mexicana , Leishmania , Antiprotozoários/farmacologia , Folhas de Planta , Terpenos/farmacologia
4.
Ars pharm ; 61(4): 209-213, oct.-dic. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-195233

RESUMO

INTRODUCCIÓN: Los extractos acuosos de las hojas de Jatropha gossypifolia L. son utilizados de forma tradicional en el tratamiento de la leishmaniasis. No existen informes concluyentes sobre su efectividad y su citotoxicidad aunque en estudios recientes ha quedado avalada la utilidad de la planta en el tratamiento de la leishmaniasis utilizando otros solventes. MÉTODO: Se determinó la actividad leishmanicida y la citotoxicidad de los extractos acuosos e hidroalcohólicos de las hojas de Jatropha gossypifolia L. utilizando el método de fluorescencia de la resazurina en promastigotes de Leishmania amazonensis y macrófagos peritoneales de ratón Balb/c respectivamente. RESULTADOS: Se obtuvieron unas concentraciones inhibitorias 50 de 0.28 Mig/mL ± 0,15 Mig/mL (n = 3) y 0.59 Mig/mL ± 0,26 Mig/mL (n = 3) para el extracto acuoso e hidroalcohólico respectivamente, aunque no se presentó actividad parasiticida a ninguna de las concentraciones evaluadas. De igual manera las concentraciones citotóxicas 50 obtenidas fueron de 0.91 Mig/mL ± 0,11 Mig/mL (n = 3) y 0.57 Mig/mL ± 0,12 Mig/ml (n = 3).CONCLUSIONES: El extracto acuoso resulta ser más eficaz y menos citotóxico frente a los promastigotes de Leishmania amazonensis. Dichos resultados avalan la utilización tópica de los extractos en su formulación tradicional para el tratamiento de la leishmaniosis cutánea


INTRODUCTION: Aqueous extracts of the leaves of Jatropha gossypifolia L. are traditionally used in the treatment of leishmaniasis. These extracts do not have conclusive reports related to their effectiveness and their cytotoxicity although in recent studies the utility of the plant in the treatment of leishmaniasis using other solvents has been supported. METHOD: The antileishmanial activity and the cytotoxicity of the aqueous and hydroalcoholic extracts of the leaves of Jatropha gossypifolia L. were determined using the resazurine fluorescence method. Both, promastigotes of Leishmania amazonensis and peritoneal macrophages of Balb/c mouse were studied. RESULTS: The half-maximal inhibitory concentration for the aqueous and hydroalcoholic extract was 0.28 Mig/mL ± 0.15 Mig/mL (n = 3) and 0.59 Mig/mL ± 0.26 Mig/mL (n = 3) respectively, although they did not show parasiticide activity at any of the evaluated concentrations. Similarly, the mean cytotoxic concentrations obtained were 0.91 Mig/mL ± 0.11 Mig/mL (n = 3) and 0.57 Mig/mL ± 0.12 Mig/ml (n = 3). CONCLUSIONS: The aqueous extract was more effective and less cytotoxic against Leishmania amazonensis promastigotes. The results obtained support the traditional use of the extracts by topical application in the treatment of cutaneous leishmaniasis


Assuntos
Animais , Camundongos , Antiprotozoários/farmacologia , Jatropha/química , Extratos Vegetais/química , Leishmania mexicana/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Folhas de Planta/química , Macrófagos Peritoneais/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Reprodutibilidade dos Testes
5.
PLoS One ; 15(11): e0241855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33156835

RESUMO

Leishmaniasis is a disease impacting public health worldwide due to its high incidence, morbidity and mortality. Available treatments are costly, lengthy and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is warranted and natural products demonstrate promising activity. This study investigated the activity of Connarus suberosus extracts and compounds against Leishmania species. Several C. suberosus extracts were tested against L. amazonensis promastigotes. Active and inactive extracts were analyzed by UHPLC-MS and data evaluated using a metabolomics platform, revealing an unknown neoflavonoid (connarin, 3), isolated together with the pterocarpans: hemileiocarpin (1) and leiocarpin (2). The aforementioned compounds (1-3), together with the benzoquinones: rapanone (4), embelin (5) and suberonone (6) previously isolated by our group from the same species, were tested against: (i) L. amazonensis and L. infantum promastigotes, and (ii) L. amazonensis intracellular amastigotes, with the most active compound (3) also tested against L. infantum amastigotes. Cytotoxicity against murine peritoneal macrophages was also investigated. Compounds 2 and 3 presented an IC50 33.8 µM and 11.4 µM for L. amazonensis promastigotes; and 44.3 µM and 13.3 µM for L. infantum promastigotes, respectively. For L. amazonensis amastigotes, the IC50 of 2 was 20.4 µM with a selectivity index (SI) of 5.7, while the IC50 of 3 was 2.9 µM with an SI of 6.3. For L. infantum amastigotes, the IC50 of 3 was 7.7 µM. Compounds 2 and 3 presented activity comparable with the miltefosine positive control, with compound 3 found to be 2-4 times more active than the positive control, depending on the Leishmania species and form. The extracts and isolated compounds showed moderate toxicity against macrophages. Compounds 2 and 3 altered the mitochondrial membrane potential (ΔΨm) and neutral lipid body accumulation, while 2 also impacted plasma membrane permeabilization, culminating in cellular disorder and parasite death. Transmission electron microscopy of L. amazonensis promastigotes treated with compound 3 confirmed the presence of lipid bodies. Leiocarpin (2) and connarin (3) demonstrated antileishmanial activity. This study provides knowledge of natural products with antileishmanial activity, paving the way for prototype development to fight this neglected tropical disease.


Assuntos
Connaraceae/química , Flavonoides/farmacologia , Metabolômica/métodos , Extratos Vegetais/farmacologia , Animais , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Flavonoides/química , Flavonoides/isolamento & purificação , Leishmania mexicana/efeitos dos fármacos , Leishmania mexicana/crescimento & desenvolvimento , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/parasitologia , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
6.
An Acad Bras Cienc ; 92(suppl 2): e20180968, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33146273

RESUMO

Leishmaniasis is a neglected disease caused by Leishmania. Chemotherapy remains the mainstay for leishmaniasis control; however, available drugs fail to provide a parasitological cure, and are associated with high toxicity. Natural products are promising leads for the development of novel chemotherapeutics against leishmaniasis. This work investigated the leishmanicidal properties of ethanolic extract of Croton blanchetianus (EECb) on Leishmania infantum and Leishmania amazonensis, and found that EECb, rich in terpenic compounds, was active against promastigote and amastigote forms of both Leishmania species. Leishmania infantum promastigotes and amastigotes presented IC50 values of 208.6 and 8.8 µg/mL, respectively, whereas Leishmania amazonensis promastigotes and amastigotes presented IC50 values of 73.6 and 3.1 µg/mL, respectively. Promastigotes exposed to EECb (100 µg/mL) had their body cellular volume reduced and altered to a round shape, and the flagellum was duplicated, suggesting that EECb may interfere with the process of cytokinesis, which could be the cause of the decline in the parasite multiplication rate. Regarding possible EECb targets, a marked depolarization of the mitochondrial membrane potential was observed. No cytotoxic effects of EECb were observed in murine macrophages at concentrations below 60 µg/mL, and the CC50 obtained was 83.8 µg/mL. Thus, the present results indicated that EECb had effective and selective effects against Leishmania infantum and Leishmania amazonensis, and that these effects appeared to be mediated by mitochondrial dysfunction.


Assuntos
Antiprotozoários , Croton , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias , Extratos Vegetais/farmacologia
7.
Mem Inst Oswaldo Cruz ; 115: e200303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33146255

RESUMO

Giardiasis is an infectious disease caused by Giardia duodenalis. The pro-drug metronidazole (MTZ) is the first-line treatment for giardiasis. Parasite's proteins as pyruvate:ferredoxin oxidoreductase (PFOR), ferredoxin (Fd), nitroreductase-1 (NR-1) and thioredoxin reductase (TrxR) participate in MTZ activation. Here, we showed Giardia trophozoites long-term exposed to MTZ presented higher IC50 than controls, showing the drug influenced the parasite survival. That reduction in MTZ's susceptibility does not seem to be related to mutations in the genes pfor, fd, nr-1 or trxr. It points that different mechanism as alterations in other metabolic pathways can account for Giardia resistance to MTZ therapy.


Assuntos
Antiprotozoários , Resistência a Medicamentos/genética , Giardia lamblia , Metronidazol/farmacologia , Pró-Fármacos , Ativação Metabólica , Antiprotozoários/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/genética , Nucleotídeos
8.
Biomolecules ; 10(11)2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33147723

RESUMO

Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.


Assuntos
Antivirais/farmacologia , Triterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Antiprotozoários/química , Antiprotozoários/farmacologia , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Plantas/química , Triterpenos/química , Triterpenos/metabolismo
9.
Chem Biol Interact ; 332: 109296, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33096056

RESUMO

Leishmaniasis is a parasitic neglected tropical disease and result in a broad spectrum of clinical manifestations, ranging from a single ulceration to a progressive and fatal visceral disease. Comprising a limited and highly toxic therapeutic arsenal, new treatments are urgently needed. Targeting delivery of drugs has been a promising approach for visceral leishmaniasis (VL). Phosphatidylserine-liposomes have demonstrated superior efficacy in VL, targeting intracellular parasites in host cells through macrophage scavenger receptors. In this work, we investigated the in vitro and in vivo efficacy of the antihelminthic drug nitazoxanide in a nanoliposomal formulation against Leishmania (L.) infantum. Physicochemical parameters of liposomes containing nitazoxanide (NTZ-LP) were determined by dynamic light scattering and small angle X-ray scattering. The efficacy of the formulation was verified in an intracellular amastigote model and in an experimental hamster model. Our findings showed that NTZ-LP was able to eliminate the amastigotes inside the host cell with an IC50 value of 16 µM. NTZ-LP was labelled a fluorescent probe and by spectrofluorimetry, we observed that the infected macrophages internalized similar levels of the drug to the uninfected cells. The confocal microscopy images confirmed the uptake and demonstrated a diffuse distribution of the NTZ-LP in the cytoplasm of Leishmania-infected macrophages, with the vesicles in a closer proximity to the parasites. For the in vivo efficacy, the liposomal NTZ-LP was administrated intraperitoneally to Leishmania-infected hamsters for 10 consecutive days at 2 mg/kg/day. By qPCR we demonstrated a reduction of the parasite burden by 82% and 50% in the liver (p < 0.05) and spleen (p < 0.05), respectively. NTZ (non-liposomal) was administered at 100 mg/kg/day per oral (p.o.) for the same period, but demonstrated no efficacy. This liposomal formulation ensured a targeting delivery of NTZ to the intracellular parasites, resulting in an good efficacy at a low dose in animals, and it may represent a new candidate therapy for VL.


Assuntos
Espaço Intracelular/parasitologia , Leishmania infantum/efeitos dos fármacos , Lipossomos/química , Nanopartículas/química , Fosfatidilserinas/metabolismo , Tiazóis/farmacologia , Animais , Antiprotozoários/farmacologia , Difusão Dinâmica da Luz , Feminino , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Masculino , Mesocricetus , Camundongos Endogâmicos BALB C , Espalhamento a Baixo Ângulo , Eletricidade Estática , Difração de Raios X
10.
Int J Nanomedicine ; 15: 8167-8173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116522

RESUMO

Introduction: This study aims to assess the efficacy of silver nanoparticles (Ag Nps) alone and combined with metronidazole (Ag Nps + MTZ) as potential alternative therapeutic agents for Blastocystis hominis. Methods: The parasites were challenged with Ag Nps, Ag Nps + MTZ and MTZ. To assess the efficacy of drugs, counting of viable parasites was done after 1, 2, and 3 hours of adding the drugs. Results: Blastocystis hominis count was reduced by 20.72%, 28.23%, and 18.92% after one hour of adding Ag Nps, Ag Nps + MTZ, and MTZ, respectively. Cysts count was further reduced by 51.49%, 61.61%, and 40.78% after 2 hours and by 71.69%, 79.67%, and 62.65% after 3 hours of adding the drugs in the same order, respectively. Conclusion: There was a statistically significant difference (P<0.05) in the in vitro growth inhibition of the parasite over the different time intervals when using the tested drugs against the control drug.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Blastocystis hominis/efeitos dos fármacos , Nanopartículas Metálicas , Prata/química , Prata/farmacologia , Blastocystis hominis/crescimento & desenvolvimento , Interações Medicamentosas , Humanos , Metronidazol/farmacologia
11.
Ann Parasitol ; 63(3): 295-302, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33128446

RESUMO

Visceral leishmaniosis is one of the most fatal old-world neglected disease with estimated 90 thousand worldwide cases emerge each year. In Iraq, the cutaneous and visceral form are endemic but available chemotherapies are either toxic with diverse side effects, expensive available drugs or parasite resistant is arising. Artemisinin (ART) is a semi-synthetic compound which proved its effectiveness against protozoan parasites, such as malaria and Leishmania. In this study, the efficacy of different concentrations of pure artemisinin was screened in vitro against promastigotes and axenic amastigotes by MTT assay after 24, 48 and 27 hours follow up. In addition, the infectivity ability and number was investigated of intra-cellular Leishman bodies in treated murine peritoneal macrophages after 24 and 48 hours ART treatment. The results verified ART efficacy against the promastigotes and axenic amastigotes viability with IC50 measured after 24, 48- and 72-hours treatment. Infectivity percentage of murine macrophages and parasite burden were significantly reduced in treated cells. These findings indicate the leishmanicidal activity of ART against the Iraqi isolate of L. donovani and further in vivo study is recommended for assigning ART as a natural anti visceral leishmaniosis compound.


Assuntos
Antiprotozoários , Artemisininas , Leishmania donovani , Leishmaniose Visceral , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Iraque , Leishmaniose Visceral/tratamento farmacológico , Macrófagos , Camundongos
12.
Parasitol Res ; 119(12): 4197-4204, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33068149

RESUMO

Resistance mechanisms of Trichomonas vaginalis to metronidazole are still not well understood. It has been shown that Mycoplasma hominis has the ability to establish an endosymbiotic relationship with T. vaginalis. This study investigated the association between T. vaginalis and M. hominis symbiosis in relation to metronidazole resistance. This study included 362 pregnant women from the King Edward VIII hospital in South Africa. The women provided self-collected vaginal swabs for the diagnosis of T. vaginalis by culture. Metronidazole susceptibility using the broth-microdilution assay was performed. Detection of the 16S rRNA from M. hominis using T. vaginalis genomic DNA as the template was performed. All statistical analysis was conducted in R statistical computing software. A total of 21 culture positive isolates were obtained resulting in a prevalence of 5.8% for T. vaginalis in the study population. Under anaerobic incubation, 52.4% (11/21) of the isolates were susceptible to metronidazole (MIC ≤ 1 µg/ml). Intermediate resistance (MIC of 2 µg/ml) and full resistance (4 µg/ml) was observed in 38.1% (8/21) and 9.5% (2/21) of the isolates, respectively. The majority of the isolates 95% (19/20) were susceptible to metronidazole under aerobic conditions. Only one isolate had a MIC of 50 µg/ml. M. hominis was shown to be present in 85.7% (18/21) of the T. vaginalis isolates. However, there was no significant association between metronidazole susceptibility and T. vaginalis-M. hominis symbiosis. This study provides evidence of emerging metronidazole resistance in T. vaginalis. However, these resistance profiles were not associated with M. hominis symbiosis.


Assuntos
Resistência a Medicamentos , Metronidazol/farmacologia , Mycoplasma hominis/fisiologia , Simbiose , Trichomonas vaginalis/microbiologia , Adulto , Antiprotozoários/farmacologia , Feminino , Humanos , Mycoplasma hominis/isolamento & purificação , Testes de Sensibilidade Parasitária , Gravidez , África do Sul/epidemiologia , Vaginite por Trichomonas/epidemiologia , Vaginite por Trichomonas/microbiologia , Vaginite por Trichomonas/parasitologia , Trichomonas vaginalis/efeitos dos fármacos
13.
J Med Chem ; 63(21): 13140-13158, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33091297

RESUMO

Leishmaniases are neglected diseases that can be treated with a limited drug arsenal; the development of new molecules is therefore a priority. Recent evidence indicates that endoperoxides, including artemisinin and its derivatives, possess antileishmanial activity. Here, 1,2-dioxanes were synthesized with their corresponding tetrahydropyrans lacking the peroxide bridge, to ascertain if this group is a key pharmacophoric requirement for the antileishmanial bioactivity. Newly synthesized compounds were examined in vitro, and their mechanism of action was preliminarily investigated. Three endoperoxides and their corresponding tetrahydropyrans effectively inhibited the growth of Leishmania donovani promastigotes and amastigotes, and iron did not play a significant role in their activation. Further, reactive oxygen species were produced in both endoperoxide- and tetrahydropyran-treated promastigotes. In conclusion, the peroxide group proved not to be crucial for the antileishmanial bioactivity of endoperoxides, under the tested conditions. Our findings reveal the potential of both 1,2-dioxanes and tetrahydropyrans as lead compounds for novel therapies against Leishmania.


Assuntos
Antiprotozoários/farmacologia , Dioxanos/química , Leishmania donovani/efeitos dos fármacos , Piranos/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Cristalografia por Raios X , Dioxanos/síntese química , Dioxanos/farmacologia , Desenho de Fármacos , Humanos , Quelantes de Ferro/farmacologia , Leishmania donovani/fisiologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Conformação Molecular , Piranos/síntese química , Piranos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Células Vero
14.
Sci Rep ; 10(1): 15158, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938966

RESUMO

The combination of pyrimethamine and sulfadiazine is the standard care in cases of congenital toxoplasmosis. However, therapy with these drugs is associated with severe and sometimes life-threatening side effects. The investigation of phytotherapeutic alternatives to treat parasitic diseases without acute toxicity is essential for the advancement of current therapeutic practices. The present study investigates the antiparasitic effects of oleoresins from different species of Copaifera genus against T. gondii. Oleoresins from C. reticulata, C. duckei, C. paupera, and C. pubiflora were used to treat human trophoblastic cells (BeWo cells) and human villous explants infected with T. gondii. Our results demonstrated that oleoresins were able to reduce T. gondii intracellular proliferation, adhesion, and invasion. We observed an irreversible concentration-dependent antiparasitic action in infected BeWo cells, as well as parasite cell cycle arrest in the S/M phase. The oleoresins altered the host cell environment by modulation of ROS, IL-6, and MIF production in BeWo cells. Also, Copaifera oleoresins reduced parasite replication and TNF-α release in villous explants. Anti-T. gondii effects triggered by the oleoresins are associated with immunomodulation of the host cells, as well as, direct action on parasites.


Assuntos
Antiprotozoários/farmacologia , Fabaceae/química , Extratos Vegetais/farmacologia , Complicações Parasitárias na Gravidez/tratamento farmacológico , Toxoplasmose/complicações , Toxoplasmose/tratamento farmacológico , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/isolamento & purificação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Fabaceae/classificação , Feminino , Interações Hospedeiro-Parasita/efeitos dos fármacos , Humanos , Microscopia Eletrônica de Transmissão , Fitoterapia , Placenta/efeitos dos fármacos , Placenta/parasitologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Gravidez , Complicações Parasitárias na Gravidez/parasitologia , Espécies Reativas de Oxigênio/metabolismo , Toxoplasma/citologia , Toxoplasma/efeitos dos fármacos , Toxoplasma/patogenicidade , Toxoplasmose/parasitologia , Trofoblastos/efeitos dos fármacos , Trofoblastos/parasitologia
15.
PLoS Negl Trop Dis ; 14(8): e0008575, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866156

RESUMO

BACKGROUND: Treatment failure and resistance to the commonly used drugs remains a major obstacle for successful chemotherapy against visceral leishmaniasis (VL). Since the development of novel therapeutics involves exorbitant costs, the effectiveness of the currently available antitrypanosomatid drug suramin has been investigated as an antileishmanial, specifically for VL,in vitro and in animal model experiments. METHODOLOGY/PRINCIPAL: Leishmania donovani promastigotes were treated with suramin and studies were performed to determine the extent and mode of cell mortality, cell cycle arrest and other in vitro parameters. In addition, L. donovani infected BALB/c mice were administered suramin and a host of immunological parameters determined to estimate the antileishmanial potency of the drug. Finally, isothermal titration calorimetry (ITC) and enzymatic assays were used to probe the interaction of the drug with one of its putative targets namely parasitic phosphoglycerate kinase (LmPGK). FINDINGS: The in vitro studies revealed the potential efficacy of suramin against the Leishmania parasite. This observation was further substantiated in the in vivo murine model, which demonstrated that upon suramin administration, the Leishmania infected BALB/c mice were able to reduce the parasitic burden and also generate the host protective immunological responses. ITC and enzyme assays confirmed the binding and consequent inhibition of LmPGK due to the drug. CONCLUSIONS/SIGNIFICANCE: All experiments affirmed the efficacy of suramin against L. donovani infection, which could possibly lead to its inclusion in the repertoire of drugs against VL.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Leishmaniose Visceral/tratamento farmacológico , Suramina/farmacologia , Suramina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Concentração Inibidora 50 , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Fosfoglicerato Quinase/efeitos dos fármacos , Células RAW 264.7/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
16.
Exp Parasitol ; 218: 107987, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32891601

RESUMO

The protozoan parasite Leishmania spp. causes leishmaniases, a group of diseases creating serious health problems in many parts of the world with significant resistance to existing drugs. Insect derived antimicrobial peptides are promising alternatives to conventional drugs against several human disease-causing pathogens because they do not generate resistance. Halictine-2, a novel antimicrobial peptide from the venom of eusocial honeybee, Halictus sexcinctus showed significant anti-leishmanial activity in vitro, towards two life forms of the dimorphic parasite, the free-swimming infective metacyclic promastigotes and the intracellular amastigotes responsible for the systemic infection. The anti-leishmanial activity of the native peptide (P5S) was significantly enhanced by serine to threonine substitution at position 5 (P5T). The peptide showed a propensity to form α-helices after substitution at position-5, conferring amphipathicity. Distinct pores observed on the promastigote membrane after P5T exposure suggested a mechanism of disruption of cellular integrity. Biochemical alterations in the promastigotes after P5T exposure included generation of increased oxygen radicals with mitochondrial Ca2+ release, loss of mitochondrial membrane potential, reduction in total ATP content and increased mitochondrial mass, resulting in quick bioenergetic and chemiosmotic collapse leading to cell death characterized by DNA fragmentation. P5T was able to reduce intracellular amastigote burden in an in vitro model of Leishmania infection but did not alter the proinflammatory cytokines like TNF-α and IL-6. The ability of the P5T peptide to kill the Leishmania parasite with negligible haemolytic activity towards mouse macrophages and human erythrocytes respectively, demonstrates its potential to be considered as a future antileishmanial drug candidate.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Antiprotozoários/farmacologia , Apoptose , Leishmania tropica/efeitos dos fármacos , Substituição de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/química , Antiprotozoários/química , Venenos de Abelha/química , Cálcio/análise , Cálcio/metabolismo , Linhagem Celular , Dicroísmo Circular , Fragmentação do DNA , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Fluorometria , Humanos , Leishmania tropica/ultraestrutura , Leishmaniose Visceral/parasitologia , Macrófagos Peritoneais , Potencial da Membrana Mitocondrial , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Microscopia Eletrônica de Varredura , Mitocôndrias/química , Tamanho Mitocondrial , Espécies Reativas de Oxigênio/isolamento & purificação , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Superóxidos/isolamento & purificação
17.
Parasitol Res ; 119(12): 3929-3946, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32803335

RESUMO

Leishmaniasis are neglected diseases and a public health problem; they are caused by protozoan species belonging to the genus Leishmania and mostly influences the poor populations in many developing countries. The lack of effective medications, and an approved vaccine, high toxicity and life-threatening side effects and many cases of drug resistance reported in different countries have resulted in the necessity to discover new, efficient, inexpensive, and safe antileishmanial compounds with less or no toxicity. This increase in consumer demand of natural herbal-derived plant extracts as alternative medicines continues despite the low scientific information to establish their efficacy and safety profiles. Various studies have been conducted so far concerning the application of herbal medicines for the treatment of leishmaniasis, but research on relatively effective and low toxic substances is still needed. In this review, we have summarized recent developments and reported studies concerning about herbal and naturally derived therapeutics in the treatment of leishmaniasis, conducted by several researchers worldwide. Some of these medical herbs with promising results have undergone prospective clinical researches, but many others have either not yet been explored. Recent articles described these medical herbs and their active and important molecules, including quinones, phenolic derivatives, lignans, tannins, terpenes, and oxylipins. We searched ISI Web of Science, PubMed, SID, Scholar, Scopus, and Science Direct, and articles published up to 2019 were included. The keywords of leishmaniasis and some words associated with herbal medicines and natural products were used in our search. This review can serve as a quick reference database for researchers.


Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Animais , Produtos Biológicos/farmacologia , Terapias Complementares , Humanos , Plantas Medicinais/química , Estudos Prospectivos , Terpenos/farmacologia
18.
Parasitol Res ; 119(10): 3503-3515, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32772176

RESUMO

Malaria, babesiosis, trypanosomosis, and leishmaniasis are some of the most life-threatening parasites, but the range of drugs to treat them is limited. An effective, safe, and low-cost drug with a large activity spectrum is urgently needed. For this purpose, an aryl amino alcohol derivative called Alsinol was resynthesized, screened in silico, and tested against Plasmodium, Babesia, Trypanosoma, and Leishmania. In silico Alsinol follows the Lipinski and Ghose rules. In vitro it had schizontocidal activity against Plasmodium falciparum and was able to inhibit gametocytogenesis; it was particularly active against late gametocytes. In malaria-infected mice, it showed a dose-dependent activity similar to chloroquine. It demonstrated a similar level of activity to reference compounds against Babesia divergens, and against promastigotes, and amastigotes stages of Leishmania in vitro. It inhibited the in vitro growth of two African animal strains of Trypanosoma but was ineffective in vivo in our experimental conditions. It showed moderate toxicity in J774A1 and Vero cell models. The study demonstrated that Alsinol has a large spectrum of activity and is potentially affordable to produce. Nevertheless, challenges remain in the process of scaling up synthesis, creating a suitable clinical formulation, and determining the safety margin in preclinical models.


Assuntos
Amino Álcoois/farmacologia , Antiprotozoários/farmacologia , Amino Álcoois/síntese química , Amino Álcoois/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Babesia/efeitos dos fármacos , Babesia/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Modelos Animais de Doenças , Leishmania/efeitos dos fármacos , Leishmania/crescimento & desenvolvimento , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Plasmodium/efeitos dos fármacos , Plasmodium/crescimento & desenvolvimento , Infecções por Protozoários/tratamento farmacológico , Infecções por Protozoários/parasitologia , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos , Trypanosoma/crescimento & desenvolvimento , Células Vero
19.
Parasitol Res ; 119(9): 2991-3003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32748038

RESUMO

Visceral leishmaniasis (VL, also known as kala-azar) is a vector borne disease caused by obligate intracellular protozoan parasite Leishmania donovani. To overcome the limitations of currently available drugs for VL, molecular target-based study is a promising tool to develop new drugs to treat this neglected tropical disease. One such target we recently identified from L. donovani (Ld) genome (WGS, clinical Indian isolate; BHU 1220, AVPQ01000001) is a small GTP-binding protein, Rab6 protein. We now report a specific inhibitor of the GTPase activity of Rab6 protein of L. donovani (LdRab6) without restricting host enzyme activity. First, to understand the nature of LdRab6 protein, we generated recombinant LdRab6 mutant proteins (rLdRab6) by systematically introducing deletion (two cysteine residues at C-terminal) and mutations [single amino acid substitutions in the conserved region of GTP (Q84L)/GDP(T38N) coding sequence]. The GTPase activity of rLdRab6:GTP and rLdRab6:GDP locked mutant proteins showed ~ 8-fold and ~ 1.5-fold decreases in enzyme activity, respectively, compared to the wild type enzyme activity. The mutant protein rLdRab6:ΔC inhibited the GTPase activity. Sequence alignment analysis of Rab6 protein of L. donovani with Homo sapiens showed identical amino acids in the G conserved region (GTP/GDP-binding sites) but it differed in the C-terminal region. We then evaluated the inhibitory activity of trans-dibenzalacetone (DBA, a synthetic analog of curcumin with strong antileishmanial activity reported earlier by us) in the GTPase activity of LdRab6 protein. Comparative molecular docking analysis of DBA and specific inhibitors of Rab proteins (Lovastatin, BFA, Zoledronate, and NE10790) indicated that DBA had optimum binding affinity with LdRab6 protein. This was further confirmed by the GTPase activity of DBA-treated LdRab6 which showed a basal GTP level significantly lower than that of the wild-type rLdRab6. The results confirm that DBA inhibits the GTPase activity of LdRab6 protein from L. donovani (LdRab6), a potential target for its antileishmanial effect.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/parasitologia , Pentanonas/farmacologia , Proteínas de Protozoários/antagonistas & inibidores , Proteínas rab de Ligação ao GTP/antagonistas & inibidores , Sequência de Aminoácidos , Sítios de Ligação , Curcumina/farmacologia , Humanos , Leishmania donovani/química , Leishmania donovani/enzimologia , Leishmania donovani/genética , Leishmaniose Visceral/tratamento farmacológico , Simulação de Acoplamento Molecular , Pentanonas/química , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Alinhamento de Sequência , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
20.
J Med Chem ; 63(19): 10773-10781, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32667203

RESUMO

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.


Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmaniose Visceral/tratamento farmacológico , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia , Animais , Antiprotozoários/uso terapêutico , Cães , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/isolamento & purificação , Leishmania major/efeitos dos fármacos , Leishmania major/isolamento & purificação , Leishmaniose Visceral/parasitologia , Fígado/parasitologia , Macaca fascicularis , Camundongos , Camundongos Endogâmicos BALB C , Inibidores de Proteassoma/uso terapêutico , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Triazóis/química
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