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2.
PLoS Negl Trop Dis ; 14(1): e0008028, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986140

RESUMO

BACKGROUND: Nifurtimox eflornithine combination therapy (NECT) to treat human African trypanosomiasis (HAT), commonly called sleeping sickness, was added to the World Health Organisation's (WHO) Essential Medicines List in 2009 and to the Paediatric List in 2012. NECT was further tested and documented in a phase IIIb clinical trial in the Democratic Republic of Congo (DRC) assessing the safety, effectiveness, and feasibility of implementation under field conditions (NECT-FIELD study). This trial brought a unique possibility to examine concomitant drug management. METHODOLOGY/PRINCIPAL FINDINGS: This is a secondary analysis of the NECT-FIELD study where 629 second stage gambiense HAT patients were treated with NECT, including children and pregnant and breastfeeding women in six general reference hospitals located in two provinces. Concomitant drugs were prescribed by the local investigators as needed. Patients underwent daily evaluations, including vital signs, physical examination, and adverse event monitoring. Concomitant medication was documented from admission to discharge. Patients' clinical profiles on admission and safety profile during specific HAT treatment were similar to previously published reports. Prescribed concomitant medications administered during the hospitalization period, before, during, and immediately after NECT treatment, were mainly analgesics/antipyretics, anthelmintics, antimalarials, antiemetics, and sedatives. Use of antibiotics was reasonable and antibiotics were often prescribed to treat cellulitis and respiratory tract infections. Prevention and treatment of neurological conditions such as convulsions, loss of consciousness, and coma was used in approximately 5% of patients. CONCLUSIONS/SIGNIFICANCE: The prescription of concomitant treatments was coherent with the clinical and safety profile of the patients. However, some prescription habits would need to be adapted in the future to the evolving available pharmacopoeia. A list of minimal essential medication that should be available at no cost to patients in treatment wards is proposed to help the different actors to plan, manage, and adequately fund drug supplies for advanced HAT infected patients. TRIAL REGISTRATION NUMBER: The initial study was registered at ClinicalTrials.gov, number NCT00906880.


Assuntos
Eflornitina/uso terapêutico , Nifurtimox/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma brucei gambiense , Tripanossomíase Africana/tratamento farmacológico , República Democrática do Congo/epidemiologia , Quimioterapia Combinada , Eflornitina/administração & dosagem , Humanos , Nifurtimox/administração & dosagem , Resultado do Tratamento , Tripanossomíase Africana/epidemiologia
3.
Drugs Today (Barc) ; 55(11): 705-712, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31840685

RESUMO

On November 15, 2018, Fexinidazole Winthrop received a positive opinion from the European Medicines Agency (EMA) (under Article 58) for treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis caused by Trypanosoma gambiense (gHAT) in adults and children 6 years and older and weighing 20 or more kg. This is the first oral regimen for gHAT that is effective in treating both disease stages. Although fexinidazole has potential to simplify current therapies, it does not entirely eliminate the need for disease staging by lumbar puncture because patients with severe stage 2 disease (CSF WBC [cerebrospinal fluid white blood cells] greater than 100 cells/µL) should only be treated with fexinidazole if no other suitable treatment is available. Nausea and vomiting are a common side effect and the drug must be administered during or after the patient's main meal under direct observation by trained health personnel. Due to late relapses, the EMA recommends follow-up to 24 months after treatment.


Assuntos
Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Humanos
5.
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
6.
Onderstepoort J Vet Res ; 86(1): e1-e6, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31170783

RESUMO

African animal trypanosomosis (AAT) is caused by several species of the genus Trypanosoma, a parasitic protozoan infecting domestic and wild animals. One of the major effects of infection with pathogenic trypanosome is anaemia. Currently, the control policies for tsetse and trypanosomosis are less effective in South Africa. The only response was to block treat all infected herds and change the dip chemical to one which controls tsetse flies during severe outbreaks. This policy proved to be less effective as demonstrated by the current high level of trypanosome infections in cattle. Our objective was to study the impacts of AAT (nagana) on animal productivity by monitoring the health of cattle herds kept in tsetse and trypanosomosis endemic areas before and after an intervention that reduces the incidence of the disease. The study was conducted on a farm in northern KwaZulu-Natal which kept a commercial cattle herd. There was no history of any cattle treatment for trypanosome. All cattle were generally in poor health condition at the start of the study though the herd received regular anthelminthic treatment. A treatment strategy using two drugs, homidium bromide (ethidium) and homidium chloride (novidium), was implemented. Cattle were monitored regularly for 13 months for herd trypanosomosis prevalence (HP), herd average packed cell volume (H-PCV) and the percentage of the herd that was anaemic (HA). A total of six odour-baited H-traps were deployed where cattle grazed from January 2006 to August 2007 to monitor the tsetse population. Glossina brevipalpis Newstead and Glossina austeni Newstead were collected continuously for the entire study period. High trypanosomes HP (44%), low average H-PCV (29.5) and HA (24%) were rerecorded in the baseline survey. All cattle in the herd received their first treatment with ethidium bromide. Regular monthly sampling of cattle for the next 142 days showed a decline in HP of 2.2% - 2.8%. However, an HP of 20% was recorded by day 220 and the herd received the second treatment using novidium chloride. The HP dropped to 0.0% and HA to 0.0% by day 116 after the second treatment. The cow group was treated again by day 160 when the HP and HA were 27.3% and 11%, respectively. The same strategy was applied to the other two groups of weaners and the calves at the time when their HP reached 20%. Ethidium and novidium treatment protected cattle, that were under continuous tsetse and trypanosomosis challenge, for up to 6 months. Two to three treatments per year may be sufficient for extended protection. However, this strategy would need to be included into an integrated pest management approach combining vector control for it to be sustainable.


Assuntos
Criação de Animais Domésticos , Anti-Helmínticos/uso terapêutico , Doenças dos Bovinos/tratamento farmacológico , Controle de Insetos , Tripanossomíase Africana/veterinária , Animais , Anti-Helmínticos/administração & dosagem , Bovinos , Doenças dos Bovinos/epidemiologia , Esquema de Medicação/veterinária , Fazendas , Insetos Vetores , África do Sul/epidemiologia , Resultado do Tratamento , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Bovina/tratamento farmacológico , Moscas Tsé-Tsé
8.
Am J Trop Med Hyg ; 101(1): 123-125, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31074413

RESUMO

We report the case of a 64-year-old woman found to have urban-acquired Trypanosoma brucei (T.b.) gambiense human African trypanosomiasis (HAT) as the cause of sustained fever starting 9 months after returning to Canada from Democratic Republic of the Congo, in the context of concomitant multiple myeloma and HIV-1 coinfection. Approaches for the management of both clinical stages of T.b. gambiense HAT are well defined for endemic settings using current diagnostics and treatments. However, few data inform the diagnosis and management of patients with bone marrow suppression from active malignancy, recent anticancer therapy, or HIV coinfection. We discuss the implications of immunosuppression for diagnosis and management of T.b. gambiense HAT.


Assuntos
Infecções por HIV/complicações , HIV-1 , Mieloma Múltiplo/complicações , Trypanosoma brucei gambiense , Tripanossomíase Africana/complicações , Coinfecção , Congo/epidemiologia , Feminino , Febre , Humanos , Pessoa de Meia-Idade , Pentamidina/uso terapêutico , Viagem , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/epidemiologia
9.
PLoS Negl Trop Dis ; 13(5): e0007373, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31120889

RESUMO

Infections of humans and livestock with African trypanosomes are treated with drugs introduced decades ago that are not always fully effective and often have severe side effects. Here, the trypanosome haptoglobin-haemoglobin receptor (HpHbR) has been exploited as a route of uptake for an antibody-drug conjugate (ADC) that is completely effective against Trypanosoma brucei in the standard mouse model of infection. Recombinant human anti-HpHbR monoclonal antibodies were isolated and shown to be internalised in a receptor-dependent manner. Antibodies were conjugated to a pyrrolobenzodiazepine (PBD) toxin and killed T. brucei in vitro at picomolar concentrations. A single therapeutic dose (0.25 mg/kg) of a HpHbR antibody-PBD conjugate completely cured a T. brucei mouse infection within 2 days with no re-emergence of infection over a subsequent time course of 77 days. These experiments provide a demonstration of how ADCs can be exploited to treat protozoal diseases that desperately require new therapeutics.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Antiprotozoários/administração & dosagem , Benzodiazepinas/administração & dosagem , Pirróis/administração & dosagem , Tripanossomíase Africana/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Antiprotozoários/química , Benzodiazepinas/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/química , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/parasitologia
10.
Medicina (Kaunas) ; 55(5)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137665

RESUMO

Background and objectives: Sleeping sickness and malaria alike are insect-borne protozoan diseases that share overlapping endemic areas in sub-Saharan Africa. The causative agent for malaria has developed resistance against all currently deployed anti-malarial agents. In the case of sleeping sickness, the currently deployed therapeutic options are limited in efficacy and activity spectra, and there are very few drug candidates in the development pipeline. Thus, there is a need to search for new drug molecules with a novel mode of actions. Materials and Methods: In the current study, an in vitro screening of a library of tetralone derivatives and related benzocycloalkanones was effected against T. b. brucei and P. falciparum. Results: Several hits with low micromolar activity (0.4-8 µM) against T. b. brucei were identified. Conclusions: The identified hits have a low molecular weight (<280 Da), a low total polar surface area (<50 Ų), and a defined structure activity relationship, which all make them potential starting points for further hit optimization studies.


Assuntos
Malária/tratamento farmacológico , Tetralonas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Humanos , Malária/fisiopatologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Tetralonas/uso terapêutico , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei gambiense/patogenicidade , Tripanossomíase Africana/fisiopatologia
11.
Drug Des Devel Ther ; 13: 1179-1185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118564

RESUMO

Background: Human African Trypanosomiasis (HAT) and leishmaniasis are two of the most neglected challenging tropical diseases, caused by the kinetoplastid parasites Trypanosoma and Leishmania species, respectively. For both of these complex disease spectra, treatment options are limited and threatened by drug resistance, justifying urgent new drug discovery efforts. Purpose: In the present study we investigated the antitrypanosomal and antileishmanial activity of a series of 21 symmetrical α,ß-unsaturated carbonyl-based compounds, each featuring two 3-methoxybenzene attached to a central cyclohexanone, tetrahydro-4-pyranone scaffold or 4-piperidone ring. Structure-activity relationships were explored with respect to substitution on positions 3, 4 and 6 of the terminal 3-methoxybenzyl groups, and seven types of central ring. Results: Compounds 3a, 3o, 3s and 3t, showed broad anti-kinetoplastid activity against all species and strains tested. Conclusion: Compound 3o featuring N-methyl-4-piperidone was found to be the most potent analog and therefore can serve as a potential lead for the development of new drug candidates for trypanosomiasis and leishmaniasis.


Assuntos
Antiprotozoários/farmacologia , Compostos de Benzil/farmacologia , Leishmania/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Antiprotozoários/química , Compostos de Benzil/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Trypanosoma brucei brucei/citologia
12.
Exp Parasitol ; 201: 49-56, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31029700

RESUMO

Trypanosoma congolense is an important pathogen that wreaks havoc in the livestock industry of the African continent. This study evaluated the in vivo antitrypanosomal activity of geranylacetone and its ameliorative effect on the disease-induced anaemia and organ damages as well as its inhibitory effects against trypanosomal sialidase using in vitro and in silico techniques. Geranylacetone was used to treat T. congolense infected rats, at a dose of 50 and 100 mg/kg BW, for 14 days where it was found to reduce the parasite burden in the infected animals. Moreover, 100 mg/kg BW of geranylacetone significantly (p < 0.05) ameliorated the anaemia, hepatic and renal damages caused by the parasite. This is in addition to the alleviation of the parasite-induced hepatosplenomegaly and upsurge in free serum sialic acid levels in the infected animals which were associated with the observed anaemia amelioration by the compound. Consequently, bloodstream T. congolense sialidase was partially purified on DEAE cellulose column and inhibition kinetic studies revealed that the enzyme was inhibited by geranylacetone via an uncompetitive inhibition pattern. In silico analysis using molecular docking with Autodock Vina indicated that geranylacetone binds to trypanosomal sialidase with a minimum free binding energy of -5.8 kcal/mol which was mediated by 26 different kinds of non-covalent interactions excluding hydrogen bond whilst Asp163 and Phe421 had the highest number of the interactions. The data suggests that geranylacetone has trypanostatic activity and could protect animals against the T. congolense-induced anaemia through the inhibition of sialidase and/or the protection of the parasite-induced hepatosplenomegaly.


Assuntos
Anemia/prevenção & controle , Terpenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/parasitologia , Animais , Feminino , Coração/efeitos dos fármacos , Coração/parasitologia , Concentração Inibidora 50 , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Masculino , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Rubiaceae/química , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Terpenos/química , Terpenos/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia
13.
Int J Mol Sci ; 20(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934540

RESUMO

The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.


Assuntos
Descoberta de Drogas , Interações Hospedeiro-Parasita , Glicoproteínas de Membrana/metabolismo , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Animais , Humanos , Proteólise
14.
Eur J Med Chem ; 173: 90-98, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986574

RESUMO

As a group of biologically active compounds, polyether antibiotics (ionophores) show a broad spectrum of interesting pharmacological properties, ranging from anti-bacterial to anti-cancer activities. There is increasing evidence that ionophores, including salinomycin (SAL), and their semi-synthetic analogues are promising candidates for the development of drugs against parasitic diseases. Our previous studies have shown that esterification and amidation of the C1 carboxylate moiety of SAL provides compounds with potent activity against Trypanosoma brucei, protozoan parasites responsible for African trypanosomiasis. In this paper, we present the synthetic pathways, crystal structures and anti-trypanosomal activity of C1 esters, amides and hydroxamic acid conjugates of SAL, its C20-oxo and propargylamine analogues as well novel C1/C20 doubly modified derivatives. Evaluation of the trypanocidal and cytotoxic activity using bloodstream forms of T. brucei and human myeloid HL-60 cells revealed that the single-modified C20-oxo and propargylamine precursor molecules 10 and 16 were the most anti-trypanosomal and selective compounds with 50% growth inhibition (GI50) values of 0.037 and 0.035 µM, and selectivity indices of 252 and 300, respectively. Also the salicylhydroxamic acid conjugate of SAL (compound 9) as well as benzhydroxamic acid and salicylhydroxamic acid conjugates of 10 (compounds 11 and 12) showed promising trypanocidal activities with GI50 values between 0.032 and 0.035 µM but less favorable selectivities. The findings confirm that modification of SAL can result in derivatives with improved trypanocidal activity that might be interesting lead compounds for further anti-trypanosomal drug development.


Assuntos
Ácidos Hidroxâmicos/farmacologia , Salicilamidas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Salicilamidas/síntese química , Salicilamidas/química , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química , Células Tumorais Cultivadas
15.
Exp Parasitol ; 200: 24-29, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30898543

RESUMO

Cases of human African trypanosomiasis caused by infection with a protozoan parasite, Trypanosoma brucei, are decreasing due to enhanced surveillance and control. However, effective and safe treatments for this disease are still needed. In this study, we investigated the antitrypanosomal activity of citrus fruit peel. When 19 citrus cultivars were examined for activity against T. brucei in vitro, significant activities were observed in four closely related cultivars and a distantly related one. Among these five cultivars, "Setoka" was selected for identification of its active components due to exhibiting the highest activity. Solvent extraction and gel filtration followed by preparative thin-layer chromatography succeeded in isolating two compounds exhibiting IC50s of 4.8 and 2.4 µg/mL, respectively. The spectral data of these two compounds were well consistent with those of sinensetin and nobiletin belonging to the class of polymethoxyflavones. Authentic compounds also showed similar IC50s. These results indicate that the two polymethoxyflavones are the major active components involved in the inhibition of T. brucei proliferation and are abundant in Setoka cultivar peel compared with the levels in the other cultivars. Setoka peel and the naturally occurring polymethoxyflavones might serve as dietary components imparting resistance to T. brucei.


Assuntos
Citrus/química , Flavonas/farmacologia , Flavonoides/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Cromatografia em Gel , Relação Dose-Resposta a Droga , Flavonas/química , Flavonas/isolamento & purificação , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Concentração Inibidora 50 , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificação , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
16.
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
17.
Exp Parasitol ; 199: 40-46, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30840850

RESUMO

Human African trypanosomosis (HAT) and animal African trypanosomosis (AAT) are diseases of economic importance in humans and animals that affect more than 36 African countries. The currently available trypanocidal drugs are associated with side effects, and the parasites are continually developing resistance. Thus, effective and safe drugs are needed for the treatment of HAT and AAT. This study aimed to evaluate the effects of azithromycin (AZM) on Trypanosoma brucei brucei-infected mice. Mice were randomly divided into 7 groups consisting of a vehicle control group, 5 test groups and a diminazene aceturate (DA)-treated group. Mice were treated orally for 7 and 28 days, as short-term and long-term treatments, respectively. Short-term AZM treatment cured 23% (16 of 70) of the overall treated mice whereas long-term treatment resulted in the survival of 70% of the mice in the groups that received AZM at doses of 300 and 400 mg/kg. Trypanosomes treated in vitro with 25 µg/mL of AZM were subjected to transmission electron microscopy, which revealed the presence of increased numbers of glycosomes and acidocalcisomes in comparison to the vehicle group. The current study showed the trypanocidal effect of AZM on T. b. brucei in vivo. The demonstrated efficacy increased with an increase in treatment period and an increased concentration of AZM.


Assuntos
Anti-Infecciosos/administração & dosagem , Azitromicina/administração & dosagem , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Peso Corporal/efeitos dos fármacos , Feminino , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Parasitemia/tratamento farmacológico , Distribuição Aleatória , Taxa de Sobrevida , Fatores de Tempo , Trypanosoma brucei brucei/ultraestrutura , Tripanossomíase Africana/mortalidade
18.
Parasitol Res ; 118(5): 1533-1548, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30903349

RESUMO

There is an urgent need to discover and develop new drugs to combat parasitic diseases as Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei), and leishmaniasis (Leishmania ssp.). These diseases are considered among the 13 most unattended diseases worldwide according to the WHO. In the present work, the synthesis of 14 arylsubstituted imidazoles and its molecular docking onto sterol 14α-demethylase (CYP51) was executed. In addition, the compounds, antiprotozoal activity against T. brucei, T. cruzi, Trypanosoma brucei rhodesiense, and Leishmania infantum was evaluated. In vitro antiparasitic results of the arylsubstituted imidazoles against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum indicated that all samples from arylsubstituted imidazole compounds presented interesting antiparasitic activity to various extent. The ligands 5a, 5c, 5e, 5f, 5g, 5i, and 5j exhibited strong activity against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum with IC50 values ranging from 0.86 to 10.23 µM. Most samples were cytotoxic against MRC-5 cell lines (1.12 < CC50 < 51.09 µM) and only ligand 5c showed a good selectivity against all tested parasites. According to the results of the molecular docking, the aromatic substituents in positions 1, 4, and 5 have mainly stabilizing hydrophobic interactions with the enzyme matrix, while the oxygen from NO2, SO3H, and OH groups interacts with the Fe2+ ion of the Heme group.


Assuntos
Antiprotozoários/química , Doença de Chagas/tratamento farmacológico , Imidazóis/química , Leishmania infantum/enzimologia , Leishmaniose/tratamento farmacológico , Esterol 14-Desmetilase/química , Trypanosoma brucei brucei/enzimologia , Trypanosoma cruzi/enzimologia , Tripanossomíase Africana/tratamento farmacológico , Animais , Antiprotozoários/farmacologia , Linhagem Celular , Humanos , Imidazóis/farmacologia , Leishmania infantum/efeitos dos fármacos , Simulação de Acoplamento Molecular , Esterol 14-Desmetilase/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos
19.
Molecules ; 24(6)2019 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-30909559

RESUMO

Human African trypanosomiasis (HAT), known as sleeping sickness and caused by Trypanosoma brucei, is threatening low-income populations in sub-Saharan African countries with 61 million people at risk of infection. In order to discover new natural products against HAT, thirty-seven Vietnamese essential oils (EOs) were screened for their activity in vitro on Trypanosoma brucei brucei (Tbb) and cytotoxicity on mammalian cells (WI38, J774). Based on the selectivity indices (SIs), the more active and selective EOs were analyzed by gas chromatography. The anti-trypanosomal activity and cytotoxicity of some major compounds (isolated or commercial) were also determined. Our results showed for the first time the selective anti-trypanosomal effect of four EOs, extracted from three Zingiberaceae species (Curcuma longa, Curcuma zedoaria, and Zingiber officinale) and one Lauraceae species (Litsea cubeba) with IC50 values of 3.17 ± 0.72, 2.51 ± 1.08, 3.10 ± 0.08, and 2.67 ± 1.12 nL/mL respectively and SI > 10. Identified compounds accounted for more than 85% for each of them. Among the five major components of Curcuma longa EO, curlone is the most promising anti-trypanosomal candidate with an IC50 of 1.38 ± 0.45 µg/mL and SIs of 31.7 and 18.2 compared to WI38 and J774 respectively.


Assuntos
Curcuma/química , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , África , África do Norte , Animais , Proliferação de Células/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Mamíferos , Óleos Voláteis/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Óleos Vegetais/química , Trypanosoma brucei brucei/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia
20.
Bioorg Med Chem ; 27(8): 1517-1528, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30833159

RESUMO

Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited IC50s below 5 µM inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.


Assuntos
Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Animais , Desenho de Fármacos , Descoberta de Drogas , Células HEK293 , Humanos , Camundongos , Células RAW 264.7 , Tripanossomíase Africana/tratamento farmacológico
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