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1.
Nat Commun ; 11(1): 3799, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732892

RESUMO

Plasmodium falciparum in pregnancy is a major cause of adverse pregnancy outcomes. We combine performance estimates of standard rapid diagnostic tests (RDT) from trials of intermittent screening and treatment in pregnancy (ISTp) with modelling to assess whether screening at antenatal visits improves upon current intermittent preventative therapy with sulphadoxine-pyrimethamine (IPTp-SP). We estimate that RDTs in primigravidae at first antenatal visit are substantially more sensitive than in non-pregnant adults (OR = 17.2, 95% Cr.I. 13.8-21.6), and that sensitivity declines in subsequent visits and with gravidity, likely driven by declining susceptibility to placental infection. Monthly ISTp with standard RDTs, even with highly effective drugs, is not superior to monthly IPTp-SP. However, a hybrid strategy, recently adopted in Tanzania, combining testing and treatment at first visit with IPTp-SP may offer benefit, especially in areas with high-grade SP resistance. Screening and treatment in the first trimester, when IPTp-SP is contraindicated, could substantially improve pregnancy outcomes.


Assuntos
Malária Falciparum/diagnóstico , Malária Falciparum/prevenção & controle , Programas de Rastreamento/métodos , Complicações Parasitárias na Gravidez/prevenção & controle , Cuidado Pré-Natal/métodos , Antimaláricos/uso terapêutico , Combinação de Medicamentos , Feminino , Política de Saúde , Humanos , Malária Falciparum/tratamento farmacológico , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Gravidez , Complicações Parasitárias na Gravidez/tratamento farmacológico , Primeiro Trimestre da Gravidez , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Tanzânia , Organização Mundial da Saúde
2.
Am J Trop Med Hyg ; 103(3): 1100-1106, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32588794

RESUMO

The emergence and spread of resistance in Plasmodium falciparum to the frontline treatment artemisinin-based combination therapies in Southeast Asia require close monitoring of the situation. Here, we collected 36 clinical samples of P. falciparum from the China-Myanmar border in 2014-2016, adapted these parasites to continuous culture, and performed in vitro drug assays on seven antimalarial drugs. Data for 23 parasites collected in 2010 and 2012 from the same area reported in an early study were used to assess longitudinal changes in drug sensitivity. Parasites remained highly resistant to chloroquine (CQ) and pyrimethamine, whereas they were generally sensitive to mefloquine (MFQ), lumefantrine (LMF), naphthoquine (NQ), and pyronaridine (PND). Parasites showed a similar temporal trend in sensitivity to CQ, NQ, and PND, with gradual reduction in the half-maximal inhibitory concentrations (IC50s) after 2012. The IC50s to the aminoalcohol drugs MFQ, LMF, and quinine (QN) all significantly declined in 2014, followed by various degrees of increase in 2016. Pyrimethamine displayed a continuous increase in IC50 over the years. The Dd2-like P. falciparum chloroquine-resistant transporter mutations were fixed or nearly fixed in the parasite population. The P. falciparum multidrug resistance 1 F1226Y mutation was detected in 80% parasites in 2016 and associated with reduced sensitivity to LMF and QN (P < 0.05). The N51I in P. falciparum dihydrofolate reductase and K540E/N and A581G in P. falciparum dihydropteroate synthase that are associated with antifolate resistance were either fixed or were approaching fixation in recent years. This study provides an updated picture and temporal trend of antimalarial drug resistance in the China-Myanmar border region, which will serve as a reference for antimalarial treatment.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos/genética , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Artemisininas/farmacologia , China/epidemiologia , Cloroquina/farmacologia , Monitoramento Epidemiológico , Humanos , Lumefantrina/farmacologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Mefloquina/farmacologia , Proteínas de Membrana Transportadoras/genética , Mianmar/epidemiologia , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Pirimetamina/farmacologia , Quinina/farmacologia
3.
PLoS Negl Trop Dis ; 14(6): e0008255, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32530913

RESUMO

BACKGROUND: Vivax malaria is an important public health problem in the Greater Mekong Subregion (GMS), including the China-Myanmar border. Previous studies have found that Plasmodium vivax has decreased sensitivity to antimalarial drugs in some areas of the GMS, but the sensitivity of P. vivax to antimalarial drugs is unclear in the China-Myanmar border. Here, we investigate the drug sensitivity profile and genetic variations for two drug resistance related genes in P. vivax isolates to provide baseline information for future drug studies in the China-Myanmar border. METHODOLOGY/PRINCIPAL FINDINGS: A total of 64 P. vivax clinical isolates collected from the China-Myanmar border area were assessed for ex vivo susceptibility to eight antimalarial drugs by the schizont maturation assay. The medians of IC50 (half-maximum inhibitory concentrations) for chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate, artemether, dihydroartemisinin were 84.2 nM, 34.9 nM, 4.0 nM, 22.3 nM, 41.4 nM, 2.8 nM, 2.1 nM and 2.0 nM, respectively. Twelve P. vivax clinical isolates were found over the cut-off IC50 value (220 nM) for chloroquine resistance. In addition, sequence polymorphisms in pvmdr1 (P. vivax multidrug resistance-1), pvcrt-o (P. vivax chloroquine resistance transporter-o), and difference in pvmdr1 copy number were studied. Sequencing of the pvmdr1 gene in 52 samples identified 12 amino acid substitutions, among which two (G698S and T958M) were fixed, M908L were present in 98.1% of the isolates, while Y976F and F1076L were present in 3.8% and 78.8% of the isolates, respectively. Amplification of the pvmdr1 gene was only detected in 4.8% of the samples. Sequencing of the pvcrt-o in 59 parasite isolates identified a single lysine insertion at position 10 in 32.2% of the isolates. The pvmdr1 M908L substitutions in pvmdr1 in our samples was associated with reduced sensitivity to chloroquine, mefloquine, pyronaridine, piperaquine, quinine, artesunate and dihydroartemisinin. CONCLUSIONS: Our findings depict a drug sensitivity profile and genetic variations of the P. vivax isolates from the China-Myanmar border area, and suggest possible emergence of chloroquine resistant P. vivax isolates in the region, which demands further efforts for resistance monitoring and mechanism studies.


Assuntos
Antimaláricos/farmacologia , Resistência a Medicamentos , Malária Vivax/parasitologia , Proteínas de Membrana Transportadoras/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/efeitos dos fármacos , Polimorfismo Genético , Proteínas de Protozoários/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China , Feminino , Genótipo , Humanos , Lactente , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Mianmar , Testes de Sensibilidade Parasitária , Plasmodium vivax/isolamento & purificação , Análise de Sequência de DNA , Adulto Jovem
4.
Parasitol Res ; 119(7): 2263-2274, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32462293

RESUMO

Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which makes the development of new drugs urgent. To achieve this goal, the integration of kinetic and DSF assays against parasitic validated targets, along with phenotypic assays, can help the identification and optimization of bioactive compounds. Pteridine reductase 1 (PTR1), a validated target in Leishmania sp., is responsible for the reduction of folate and biopterin to tetrahydrofolate and tetrahydrobiopterin, respectively, both of which are essential for cell growth. In addition to the in vitro evaluation of 16 thiazolidine-2,4-dione derivatives against Leishmania major PTR1 (LmPTR1), using the differential scanning fluorimetry (ThermoFluor®), phenotypic assays were employed to evaluate the compound effect over Leishmania braziliensis (MHOM/BR/75/M2903) and Leishmania infantum (MHOM/BR/74/PP75) promastigotes viability. The ThermoFluor® results show that thiazolidine-2,4-dione derivatives have micromolar affinity to the target and equivalent activity on Leishmania cells. 2b is the most potent compound against L. infantum (EC50 = 23.45 ± 4.54 µM), whereas 2a is the most potent against L. braziliensis (EC50 = 44.16 ± 5.77 µM). This result suggests that lipophilic substituents on either-meta and/or-para positions of the benzylidene ring increase the potency against L. infantum. On the other hand, compound 2c (CE50 = 49.22 ± 7.71 µM) presented the highest selectivity index.


Assuntos
Antiprotozoários/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Animais , Antiprotozoários/química , Humanos , Leishmania braziliensis/enzimologia , Leishmania infantum/enzimologia , Oxirredutases/antagonistas & inibidores , Testes de Sensibilidade Parasitária , Tiazolidinedionas/química
5.
Parasitol Res ; 119(7): 2351-2358, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32451717

RESUMO

Naegleria fowleri causes a deadly infection known as primary amoebic meningoencephalitis (PAM). To our knowledge, there are very few transcriptome studies conducted on these brain-eating amoebae, despite rise in the number of cases. Although the Naegleria genome has been sequenced, currently, it is not well annotated. Transcriptome level studies are needed to help understand the pathology and biology of this fatal parasitic infection. Recently, we showed that nanoparticles loaded with the flavonoid Hesperidin (HDN) are potential novel antimicrobial agents. N. fowleri trophozoites were treated with and without HDN-conjugated with silver nanoparticles (AgNPs) and silver only, and then, 50% minimum inhibitory concentration (MIC) was determined. The results revealed that the MIC of HDN-conjugated AgNPs was 12.5 microg/mL when treated for 3 h. As no reference genome exists for N. fowleri, de novo RNA transcriptome analysis using RNA-Seq and differential gene expression analysis was performed using the Trinity software. Analysis revealed that more than 2000 genes were differentially expressed in response to N. fowleri treatment with HDN-conjugated AgNPs. Some of the genes were linked to oxidative stress response, DNA repair, cell division, cell signalling and protein synthesis. The downregulated genes were linked with processes such as protein modification, synthesis of aromatic amino acids, when compared with untreated N. fowleri. Further transcriptome studies will lead to understanding of genetic mechanisms of the biology and pathogenesis and/or the identification of much needed drug candidates.


Assuntos
Infecções Protozoárias do Sistema Nervoso Central/parasitologia , Hesperidina/farmacocinética , Naegleria fowleri/genética , Prata/farmacologia , Transcriptoma/genética , Animais , Divisão Celular/genética , Reparo do DNA/genética , Perfilação da Expressão Gênica , Hesperidina/metabolismo , Humanos , Nanopartículas Metálicas , Estresse Oxidativo/genética , Testes de Sensibilidade Parasitária , RNA-Seq , Prata/metabolismo
6.
Parasitol Res ; 119(6): 1857-1871, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32350589

RESUMO

Antimony is an important drug for the treatment of Leishmania parasite infections. In several countries, the emergence of drug-resistant Leishmania species has reduced the effectiveness of this drug. The mechanism of clinical drug resistance is unclear. The aim of this work was to identify mitochondrial proteome alterations associated with resistance against antimonial. A combination of cell fractionation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and Label-Free Quantification was used to characterize the mitochondrial protein composition of Leishmania tropica field isolates resistant and sensitive to meglumine antimoniate. LC-MS/MS analysis resulted in the identification of about 1200 proteins of the Leishmania tropica mitochondrial proteome. Various criteria were used to allocate about 40% proteins to mitochondrial proteome. Comparative quantitative proteomic analysis of the sensitive and the resistant strains showed proteins with differential abundance in resistance species are involved in TCA and aerobic respiration enzymes, stress proteins, lipid metabolism enzymes, and translation. These results showed that the mechanism of antimony resistance in Leishmania spp. field isolate may be associated with alteration in enzymes involved in mitochondrial pathways.


Assuntos
Antiprotozoários/farmacologia , Leishmania tropica/efeitos dos fármacos , Antimoniato de Meglumina/farmacologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Linhagem Celular , Cromatografia Líquida , Resistência a Medicamentos , Leishmania tropica/isolamento & purificação , Leishmania tropica/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Proteoma , Proteômica , Espectrometria de Massas em Tandem
7.
J Med Chem ; 63(9): 4929-4956, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32248693

RESUMO

Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 (1) showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus Plasmodium DHODH and Plasmodium parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best lead DSM502 (37) showed in vivo efficacy at similar levels of blood exposure to 1, although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.


Assuntos
Antimaláricos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Pirróis/uso terapêutico , Animais , Antimaláricos/síntese química , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Linhagem Celular Tumoral , Cristalografia por Raios X , Cães , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/enzimologia , Ligação Proteica , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Ratos , Relação Estrutura-Atividade
8.
ScientificWorldJournal ; 2020: 7821310, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292295

RESUMO

Agrimonia asiatica is a perennial plant with deep green color and covered with soft hairs and has a slightly aromatic odor. This genus Agrimonia has been used in traditional medicines of China, Greece, and European countries. It was mainly used as a haemostatic, a tonic for asthenia, and an astringent for diarrhea. Agrimony is part of the division Magnoliophyta; class is represented by order Rosales, family Rosaceae, of the genus Agrimonia. Family Rosaceae-or pink eels-is one of the largest families of flowering plants, including about 100 genera and 3000 species. Rosaceae is common in almost all areas of the globe where flowering plants can grow, but most of them are concentrated in the temperate and subtropical zones of the Northern Hemisphere. Phytochemical investigation on ethanolic extract of A. asiatica led to isolation of four flavonoid derivatives (kaempferol-3-glycoside, quercetin-3-O-α-arabinofuranosyl-ß-D-galactopyranoside, 3-O-kaempherol 2,3-di-O-acetyl-4-O-(cis-p-coumaroyl)-6-O-(trans-p-coumaroyl)-ß-D-glucosopyranoside, and catechin) alongside of sucrose. All the extracts, fractions, and isolated compounds were tested for antimicrobial and antiplasmodial activities. We also studied the chemical composition of essential oil obtained from the aerial part of A. asiatica. The essential oil constituents from the aerial part of A. asiatica were obtained using a steam-distillation method in wild growing conditions in Kazakhstan. The essential oil extracted from the aerial part of the plant was analyzed by gas chromatography-mass spectroscopy and its major components amounting to 100% were found to be ß-selinene (36.370%), α-panasinsene (21.720%), hexadecanoic acid (7.839%), and 1,2-nonadiene (6.199%). Neither the extract nor the isolated compounds showed antimicrobial and antiplasmodial activities.


Assuntos
Agrimonia/química , Anti-Infecciosos/farmacologia , Antiprotozoários/farmacologia , Óleos Voláteis/farmacologia , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Óleos Voláteis/química , Óleos Voláteis/isolamento & purificação , Testes de Sensibilidade Parasitária , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
9.
Artigo em Inglês | MEDLINE | ID: mdl-32234669

RESUMO

Giardia duodenalis, the most prevalent human intestinal parasite causes the disease, giardiasis. On an annual basis G. duodenalis infects ~1 billion people, of which ~280 million develop symptomatic disease. Giardiasis can be severe and chronic, causing malnutrition, stunted growth and poor cognitive development in children. Current treatment options rely on drugs with declining efficacy and side-effects. To improve the health and well-being of millions of people world-wide, new anti-Giardia drugs with different modes of action to currently used drugs are required. The Medicines for Malaria Venture's Pathogen Box, a collection of bio-active compounds specifically chosen to stimulate infectious disease drug discovery, represents an opportunity for the discovery of new anti-Giardia agents. While the anti-Giardia activity of Pathogen Box compounds has been reported, this work failed to identify known anti-Giardia controls within the compound set. It also reported the activity of compounds previously screened and shown to be inactive by others, suggesting data may be inaccurate. Given these concerns the anti-Giardia activity of Pathogen Box compounds was re-assessed in the current study. Data from this work identified thirteen compounds with anti-Giardia IC50 values ≤2 µM. Five of these compounds were reference compounds (marketed drugs with known anti-microbial activity), or analogues of compounds with previously described anti-Giardia activity. However, eight, including MMV676358 and MMV028694, which demonstrated potent sub-µM IC50s against assemblage A, B and metronidazole resistant parasites (0.3 µM and 0.9 µM respectively), may represent new leads for future drug development. Interestingly, only four of these compounds were identified in the previously reported Pathogen Box screen highlighting the importance of assay selection and design when assessing compounds for activity against infectious agents.


Assuntos
Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Bioensaio/métodos , Descoberta de Drogas/métodos , Giardia lamblia/efeitos dos fármacos , Giardia/efeitos dos fármacos , Descoberta de Drogas/instrumentação , Giardíase/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Prevalência
10.
Nat Protoc ; 15(6): 1881-1921, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341577

RESUMO

Despite decades of research, little is known about the cellular targets and the mode of action of the vast majority of antimalarial drugs. We recently demonstrated that the cellular thermal shift assay (CETSA) protocol in its two variants: the melt curve and the isothermal dose-response, represents a comprehensive strategy for the identification of antimalarial drug targets. CETSA enables proteome-wide target screening for unmodified antimalarial compounds with undetermined mechanisms of action, providing quantitative evidence about direct drug-protein interactions. The experimental workflow involves treatment of P. falciparum-infected erythrocytes with a compound of interest, heat exposure to denature proteins, soluble protein isolation, enzymatic digestion, peptide labeling with tandem mass tags, offline fractionation, and liquid chromatography-tandem mass spectrometry analysis. Methodological optimizations necessary for the analysis of this intracellular parasite are discussed, including enrichment of parasitized cells and hemoglobin depletion strategies to overcome high hemoglobin abundance in the host red blood cells. We outline an effective data processing workflow using the mineCETSA R package, which enables prioritization of drug-target candidates for follow-up studies. The entire protocol can be completed within 2 weeks.


Assuntos
Antimaláricos/farmacologia , Malária Falciparum/parasitologia , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Descoberta de Drogas/métodos , Eritrócitos/parasitologia , Humanos , Malária Falciparum/metabolismo , Terapia de Alvo Molecular/métodos , Testes de Sensibilidade Parasitária/métodos , Plasmodium falciparum/metabolismo , Proteoma/metabolismo
11.
Eur J Med Chem ; 193: 112215, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32179331

RESUMO

Malaria remains a serious worldwide health danger and massive economic trouble to disease-endemic nations. Presently, 250 million of malarial cases are expected worldwide. The emergence of fighting of the Plasmodium parasite against the first-line antimalarial drugs has fueled research attention in the way of designing new scaffolds as well as strategies to counter the drug resistance. Chalcones are simple and well-known analogs, which were found in a huge number of natural compounds and also been prepared according to their suitable synthetic approaches. This review illustrates the current progresses on structure-activity relationship (SAR) and mechanism of diverse types of chalcone derivatives that play a significant role for the development of novel safe, less toxic and highly active antimalarials. This present mini-review will be useful to scientists in research fields of medicinal chemistry, organic synthesis, and also various biological applications particularly for the development of novel antiplasmodial and antimalarial agents.


Assuntos
Antimaláricos/farmacologia , Chalcona/farmacologia , Descoberta de Drogas , Malária/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/química , Chalcona/síntese química , Chalcona/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
12.
J Med Chem ; 63(7): 3723-3736, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32134263

RESUMO

Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.


Assuntos
Adamantano/uso terapêutico , Ácidos Carboxílicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Esquistossomicidas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/toxicidade , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidade , Linhagem Celular Tumoral , Feminino , Células HEK293 , Compostos Heterocíclicos com 1 Anel/síntese química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/toxicidade , Humanos , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacocinética , Esquistossomicidas/toxicidade , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/toxicidade , Relação Estrutura-Atividade
13.
J Med Chem ; 63(7): 3485-3507, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196340

RESUMO

Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of Africa. In this manuscript we describe the optimization of a family of phtalazinone derivatives. Phosphodiesterases have emerged as attractive molecular targets for a novel treatment for a variety of neglected parasitic diseases. Compound 1 resulted in being a potent TbrPDEB1 inhibitor with interesting activity against T. brucei in a phenotypic screen. Derivative 1 was studied in an acute in vivo mouse disease model but unfortunately showed no efficacy due to low metabolic stability. We report structural modifications to achieve compounds with an improved metabolic stability while maintaining high potency against TbrPDEB1 and T. brucei. Compound 14 presented a good microsomal stability in mouse and human microsomes and provides a good starting point for future efforts.


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Ftalazinas/farmacologia , Tripanossomicidas/farmacologia , Animais , Cristalografia por Raios X , Estabilidade de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Ftalazinas/síntese química , Ftalazinas/metabolismo , Ligação Proteica , Proteínas de Protozoários/metabolismo , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismo , Trypanosoma brucei brucei/efeitos dos fármacos
14.
J Fr Ophtalmol ; 43(4): 330-333, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32151474

RESUMO

Acanthamoeba keratitis due to a genus of free-living amoebae is a severe corneal infection. Treatment of this disease is based on the combined use of antiseptics and other drugs, including azoles. We tested isavuconazole, the latest marketed azole, in vitro, against A. castellanii, A. lenticulata and A. hatchetti. Our results show that isavuconazole presents slight amoebistatic activity against A. castellanii trophozoites but no cysticidal activity. Isavuconazole could be used only in association for management of AK due to A. castellanii.


Assuntos
Ceratite por Acanthamoeba/parasitologia , Acanthamoeba/efeitos dos fármacos , Nitrilos/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Acanthamoeba/classificação , Acanthamoeba/crescimento & desenvolvimento , Acanthamoeba/fisiologia , Ceratite por Acanthamoeba/tratamento farmacológico , Acanthamoeba castellanii/efeitos dos fármacos , Acanthamoeba castellanii/crescimento & desenvolvimento , Acanthamoeba castellanii/fisiologia , Animais , Relação Dose-Resposta a Droga , Humanos , Nitrilos/uso terapêutico , Encistamento de Parasitas/efeitos dos fármacos , Testes de Sensibilidade Parasitária , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Trofozoítos/efeitos dos fármacos
15.
J Med Chem ; 63(6): 3066-3089, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32134269

RESUMO

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is endemic in South and Central America and recently has been found in other parts of the world, due to migration of chronically infected patients. The current treatment for Chagas disease is not satisfactory, and there is a need for new treatments. In this work, we describe the optimization of a hit compound resulting from the phenotypic screen of a library of compounds against T. cruzi. The compound series was optimized to the level where it had satisfactory pharmacokinetics to allow an efficacy study in a mouse model of Chagas disease. We were able to demonstrate efficacy in this model, although further work is required to improve the potency and selectivity of this series.


Assuntos
Doença de Chagas/tratamento farmacológico , Quinazolinonas/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma cruzi/efeitos dos fármacos , Animais , Linhagem Celular , Descoberta de Drogas , Feminino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Estudo de Prova de Conceito , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinética
16.
PLoS Negl Trop Dis ; 14(3): e0008150, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32196500

RESUMO

Parasitic infections are a major source of human suffering, mortality, and economic loss, but drug development for these diseases has been stymied by the significant expense involved in bringing a drug though clinical trials and to market. Identification of single compounds active against multiple parasitic pathogens could improve the economic incentives for drug development as well as simplifying treatment regimens. We recently performed a screen of repurposed compounds against the protozoan parasite Entamoeba histolytica, causative agent of amebic dysentery, and identified four compounds (anisomycin, prodigiosin, obatoclax and nithiamide) with low micromolar potency and drug-like properties. Here, we extend our investigation of these drugs. We assayed the speed of killing of E. histolytica trophozoites and found that all four have more rapid action than the current drug of choice, metronidazole. We further established a multi-institute collaboration to determine whether these compounds may have efficacy against other parasites and opportunistic pathogens. We found that anisomycin, prodigiosin and obatoclax all have broad-spectrum antiparasitic activity in vitro, including activity against schistosomes, T. brucei, and apicomplexan parasites. In several cases, the drugs were found to have significant improvements over existing drugs. For instance, both obatoclax and prodigiosin were more efficacious at inhibiting the juvenile form of Schistosoma than the current standard of care, praziquantel. Additionally, low micromolar potencies were observed against pathogenic free-living amebae (Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba castellanii), which cause CNS infection and for which there are currently no reliable treatments. These results, combined with the previous human use of three of these drugs (obatoclax, anisomycin and nithiamide), support the idea that these compounds could serve as the basis for the development of broad-spectrum anti-parasitic drugs.


Assuntos
Anisomicina/farmacologia , Antiparasitários/farmacologia , Reposicionamento de Medicamentos , Parasitos/efeitos dos fármacos , Prodigiosina/farmacologia , Pirróis/farmacologia , Animais , Anisomicina/efeitos adversos , Anisomicina/farmacocinética , Antiparasitários/efeitos adversos , Antiparasitários/farmacocinética , Linhagem Celular , Sobrevivência Celular , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Parasitária , Prodigiosina/efeitos adversos , Prodigiosina/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Ratos
17.
PLoS Negl Trop Dis ; 14(3): e0008068, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32163414

RESUMO

Trypanosoma cruzi parasites utilise de novo pyrimidine biosynthesis to produce DNA and survive within mammalian host cells. This pathway can be hijacked to assess the replication of intracellular parasites with the exogenous addition of a DNA specific probe. To identify suitable probe compounds for this application, a collection of pyrimidine nucleoside analogues was assessed for incorporation into T. cruzi intracellular amastigote DNA using image-based technology and script-based analysis. Associated mammalian cell toxicity of these compounds was also determined against both the parasite host cells (3T3 cells) and HEK293 cells. Incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into parasite DNA was the most effective of the probes tested, with minimal growth inhibition observed following either two or four hours EdU exposure. EdU was subsequently utilised as a DNA probe, followed by visualisation with click chemistry to a fluorescent azide, to assess the impact of drugs and compounds with previously demonstrated activity against T. cruzi parasites, on parasite replication. The inhibitory profiles of these molecules highlight the benefit of this approach for identifying surviving parasites post-treatment in vitro and classifying compounds as either fast or slow-acting. F-ara-EdU resulted in <50% activity observed against T. cruzi amastigotes following 48 hours incubation, at 73 µM. Collectively, this supports the further development of pyrimidine nucleosides as chemical probes to investigate replication of the parasite T. cruzi.


Assuntos
Antiprotozoários/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Testes de Sensibilidade Parasitária/métodos , Nucleosídeos de Pirimidina/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/crescimento & desenvolvimento , Células 3T3 , Animais , Antiprotozoários/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Nucleosídeos de Pirimidina/toxicidade
18.
Molecules ; 25(3)2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033336

RESUMO

Essential oils (EOs) have for a long time been recognized to possess several different biological activities. Several among these secondary plant metabolites exhibit marked antimicrobial effects that have made their use as an antiseptic and/or preservative in food well known, since the ancient times [...].


Assuntos
Antibacterianos/farmacologia , Antiparasitários/farmacologia , Óleos Voláteis/farmacologia , Parassimpatolíticos/farmacologia , Óleos Vegetais/farmacologia , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária
19.
Eur J Med Chem ; 191: 112146, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32088496

RESUMO

In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how functionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and antitrypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC50 > 10 µM (vs 0.18 µM and 2.31 µM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 µM ≤ IC50 ≤ 2.18 µM vs IC50 = 2.31 µM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC50 > 10 µM).


Assuntos
Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Nitroimidazóis/farmacologia , Oxazóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Nitroimidazóis/síntese química , Nitroimidazóis/química , Oxazóis/síntese química , Oxazóis/química , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
20.
J Enzyme Inhib Med Chem ; 35(1): 639-649, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32048531

RESUMO

Leishmaniasis is a neglected disease caused by the protozoa Leishmania ssp. Environmental differences found by the parasites in the vector and the host are translated into cellular stress, leading to the production of heat shock proteins (Hsp). These are molecular chaperones involved in the folding of nascent proteins as well as in the regulation of gene expression, signalling events and proteostasis. Since Leishmania spp. use Hsp90 to trigger important transitions between their different stages of the life cycle, this protein family becomes a profitable target in anti-parasite drug discovery. In this work, we implemented a multidisciplinary strategy coupling molecular modelling with in vitro assays to identify small molecules able to inhibit Hsp90 from L. braziliensis (LbHsp90). Overall, we identified some compounds able to kill the promastigote form of the L. braziliensis, and to inhibit LbHsp90 ATPase activity.


Assuntos
Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Leishmania braziliensis/efeitos dos fármacos , Chaperonas Moleculares/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Adenosina Trifosfatases/antagonistas & inibidores , Adenosina Trifosfatases/metabolismo , Antiprotozoários/síntese química , Antiprotozoários/química , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas de Choque Térmico HSP90/metabolismo , Leishmania braziliensis/química , Modelos Moleculares , Chaperonas Moleculares/síntese química , Chaperonas Moleculares/química , Estrutura Molecular , Testes de Sensibilidade Parasitária , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
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