RESUMO
Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
Assuntos
Antituberculosos/farmacologia , Carbamatos/farmacologia , Compostos Heterocíclicos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Antituberculosos/química , Antituberculosos/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/química , Compostos Heterocíclicos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/metabolismo , Oximas/química , Oximas/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp3-rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by whole-genome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.
Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Anopheles/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/metabolismo , Feminino , Células Germinativas/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ratos , Compostos de Espiro/síntese química , Compostos de Espiro/metabolismo , Relação Estrutura-AtividadeRESUMO
Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biology triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clinical isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the minimum inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds. Structure-activity relationship studies identified potent compounds with good physicochemical properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines.
Assuntos
Antituberculosos/química , Pirimidinonas/química , Animais , Antituberculosos/metabolismo , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Meia-Vida , Humanos , Ferro/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microssomos/metabolismo , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Pirazóis/química , Pirimidinonas/metabolismo , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure-activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
Assuntos
Antimaláricos/química , Hemeproteínas/antagonistas & inibidores , Imidazóis/química , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/antagonistas & inibidores , Piridinas/química , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Meia-Vida , Hemeproteínas/metabolismo , Imidazóis/metabolismo , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Malária/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Piridinas/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A novel series of pyrido[1,2- a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized and evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, and in vivo antimalarial efficacy in a mouse model. Oral administration of one of the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% in Plasmodium berghei-infected mice, with a mean survival period of 16 days post-treatment. The in vivo efficacy of these derivatives is likely a consequence of their active metabolites, two of which showed potent in vitro antiplasmodium activity against chloroquine-sensitive and multidrug-resistant Plasmodium falciparum ( P. falciparum) strains. Rapid metabolism was observed for all the analogues with <40% of parent compound remaining after 30 min of incubation in liver microsomes. RM trapping studies detected glutathione adducts only in derivatives bearing 4-aminophenol moiety, with fragmentation signatures showing that this conjugation occurred on the phenyl ring of the Mannich base side chain. As with amodiaquine (AQ), interchanging the positions of the 4-hydroxyl and Mannich base side group or substituting the 4-hydroxyl with fluorine appeared to block bioactivation of the AQ-like derivatives though at the expense of antiplasmodium activity, which was significantly lowered.
Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/química , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Malária/tratamento farmacológico , Bases de Mannich/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Avaliação Pré-Clínica de Medicamentos , Humanos , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei , Plasmodium falciparum/fisiologia , Relação Estrutura-AtividadeRESUMO
The in vivo antimalarial efficacies of two phosphatidylinositol 4-kinase (PI4K) inhibitors, a 3,5-diaryl-2-aminopyrazine sulfoxide and its corresponding sulfone metabolite, were evaluated in the NOD-scid IL2Rγnull (NSG) murine malaria disease model of Plasmodium falciparum infection. We hypothesized that the sulfoxide would serve as a more soluble prodrug for the sulfone, which would lead to improved drug exposure with oral dosing. Both compounds had similar efficacy (90% effective dose [ED90], 0.1 mg kg-1 of body weight) across a quadruple-dose regimen. Pharmacokinetic profiling revealed rapid sulfoxide clearance via conversion to sulfone, with sulfone identified as the major active metabolite. When the sulfoxide was dosed, the exposure of the sulfone achieved was as much as 2.9-fold higher than when the sulfone was directly dosed, thereby demonstrating that the sulfoxide served as an effective prodrug for the treatment of malaria.
Assuntos
Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Parasitemia/tratamento farmacológico , Pró-Fármacos/farmacologia , Pirazinas/farmacologia , Sulfonas/farmacologia , Sulfóxidos/farmacologia , 1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , 1-Fosfatidilinositol 4-Quinase/genética , 1-Fosfatidilinositol 4-Quinase/metabolismo , Animais , Antimaláricos/sangue , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Biotransformação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Expressão Gênica , Humanos , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Parasitemia/patologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Plasmodium falciparum/crescimento & desenvolvimento , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Pirazinas/sangue , Pirazinas/síntese química , Pirazinas/farmacocinética , Sulfonas/sangue , Sulfonas/síntese química , Sulfonas/farmacocinética , Sulfóxidos/sangue , Sulfóxidos/síntese química , Sulfóxidos/farmacocinética , Resultado do TratamentoRESUMO
A lead-optimization program around a 2,6-imidazopyridine scaffold was initiated based on the two early lead compounds, 1 and 2, that were shown to be efficacious in an in vivo humanized Plasmodium falciparum NODscidIL2Rγnull mouse malaria infection model. The observation of atypical dose-response curves when some compounds were tested against multidrug resistant malaria parasite strains guided the optimization process to define a chemical space that led to typical sigmoidal dose-response and complete kill of multidrug resistant parasites. After a structure and property analysis identified such a chemical space, compounds were prepared that displayed suitable activity, ADME, and safety profiles with respect to cytotoxicity and hERG inhibition.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Piridinas/química , Piridinas/farmacologia , Absorção Fisico-Química , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Relação Dose-Resposta a Droga , Imidazóis/metabolismo , Imidazóis/farmacocinética , Camundongos , Piridinas/metabolismo , Piridinas/farmacocinética , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.
RESUMO
A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.
Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Naftiridinas/química , Naftiridinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Camundongos , Modelos Moleculares , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Plasmodium falciparum/fisiologia , Conformação Proteica , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.
Assuntos
Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacocinética , Malária/tratamento farmacológico , Plasmodium falciparum/fisiologia , Piridinas/química , Piridinas/farmacocinética , Animais , Modelos Animais de Doenças , Estabilidade de Medicamentos , Canal de Potássio ERG1/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Malária/genética , Malária/metabolismo , Camundongos , Piridinas/metabolismo , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual , Água/químicaRESUMO
Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.
Assuntos
Aminopiridinas/farmacologia , Antimaláricos/farmacologia , Fosfotransferases/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/química , Aminopiridinas/isolamento & purificação , Antimaláricos/química , Antimaláricos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Plasmodium falciparum/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificaçãoRESUMO
A BioFocus DPI SoftFocus library of â¼35â¯000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade , Administração Oral , Animais , Antituberculosos/síntese química , Proteínas Sanguíneas/metabolismo , Estabilidade de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Proteômica/métodos , Pirimidinas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Vanilla is a flavoring recovered from the cured beans of the orchid genus Vanilla. Vanilla ×tahitensis is traditionally cultivated on the islands of French Polynesia, where vanilla vines were first introduced during the nineteenth century and, since the 1960s, have been introduced to other Pacific countries such as Papua New Guinea (PNG), cultivated and sold as "Tahitian vanilla," although both sensory properties and aspect are different. From an economic point of view, it is important to ensure V. ×tahitensis traceability and to guarantee that the marketed product is part of the future protected designation of the origin "Tahitian vanilla" (PDO), currently in progress in French Polynesia. The application of metabolomics, allowing the detection and simultaneous analysis of hundreds or thousands of metabolites from different matrices, has recently gained high interest in food traceability. Here, metabolomics analysis of phenolic compounds profiles was successfully applied for the first time to V. ×tahitensis to deepen our knowledge of vanilla metabolome, focusing on phenolics compounds, for traceability purposes. Phenolics were screened through a quadrupole-time-of-flight mass spectrometer coupled to a UHPLC liquid chromatography system, and 260 different compounds were clearly evidenced and subjected to different statistical analysis in order to enable the discrimination of the samples based on their origin. Eighty-eight and twenty three compounds, with a prevalence of flavonoids, resulted to be highly discriminant through ANOVA and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) respectively. Volcano plot analysis and pairwise comparisons were carried out to determine those compounds, mainly responsible for the differences among samples as a consequence of either origin or cultivar. The samples from PNG were clearly different from the Tahitian samples that were further divided in two different groups based on the different phenolic patterns. Among the 260 compounds, metabolomics analysis enabled the detection of previously unreported phenolics in vanilla (such as flavonoids, lignans, stilbenes and other polyphenols).
RESUMO
The extensive use of praziquantel against schistosomiasis raises concerns about drug resistance. New therapeutic alternatives targeting critical pathways within the parasite are therefore urgently needed. Hemozoin formation in Schistosoma presents one such target. We assessed the in vitro antischistosomal activity of pyrido[1,2-a]benzimidazoles (PBIs) and investigated correlations with their ability to inhibit ß-hematin formation. We further evaluated the in vivo efficacy of representative compounds in experimental mice and conducted pharmacokinetic analysis on the most potent. At 10 µM, 48/57 compounds resulted in >70% mortality of newly transformed schistosomula, whereas 37 of these maintained >60% mortality of adult S. mansoni. No correlations were observed between ß-hematin inhibitory and antischistosomal activities against both larval and adult parasites, suggesting possible presence of other target(s) or a mode of inhibition of crystal formation that is not adequately modeled by the assay. The most active compound in vivo showed 58.7 and 61.3% total and female worm burden reduction, respectively. Pharmacokinetic analysis suggested solubility-limited absorption and high hepatic clearance as possible contributors to the modest efficacy despite good in vitro activity. The PBIs evaluated in this report thus merit further optimization to improve their efficacy and to elucidate their possible mode of action.
Assuntos
Benzimidazóis/farmacologia , Piridinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Modelos Animais de Doenças , Feminino , Hemeproteínas/antagonistas & inibidores , Hemeproteínas/biossíntese , Concentração Inibidora 50 , Camundongos , Praziquantel/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/metabolismo , Esquistossomose mansoni/parasitologia , Esquistossomicidas/síntese química , Esquistossomicidas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Insight into the mechanisms of intestinal transport and metabolism of aspalathin will provide important information for dose optimisation, in particular for studies using mouse models. Aspalathin transportation across the intestinal barrier (Caco-2 monolayer) tested at 1-150 µM had an apparent rate of permeability (Papp) typical of poorly absorbed compounds (1.73 × 10-6 cm/s). Major glucose transporters, sodium glucose linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2), and efflux protein (P-glycoprotein, PgP) (1.84 × 10-6 cm/s; efflux ratio: 1.1) were excluded as primary transporters, since the Papp of aspalathin was not affected by the presence of specific inhibitors. The Papp of aspalathin was also not affected by constituents of aspalathin-enriched rooibos extracts, but was affected by high glucose concentration (20.5 mM), which decreased the Papp value to 2.9 × 10-7 cm/s. Aspalathin metabolites (sulphated, glucuronidated and methylated) were found in mouse urine, but not in blood, following an oral dose of 50 mg/kg body weight of the pure compound. Sulphates were the predominant metabolites. These findings suggest that aspalathin is absorbed and metabolised in mice to mostly sulphate conjugates detected in urine. Mechanistically, we showed that aspalathin is not actively transported by the glucose transporters, but presumably passes the monolayer paracellularly.
Assuntos
Aspalathus/química , Chalconas/farmacocinética , Absorção Intestinal , Intestinos/química , Animais , Disponibilidade Biológica , Transporte Biológico , Células CACO-2 , Chalconas/administração & dosagem , Humanos , Camundongos , Permeabilidade , Extratos Vegetais/química , Urina/químicaRESUMO
Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.
Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Benzimidazóis/química , Benzimidazóis/uso terapêutico , Malária/tratamento farmacológico , Malária/parasitologia , Plasmodium berghei/efeitos dos fármacos , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Camundongos , Plasmodium berghei/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Euterpe oleracea (açaí) is a palm tree well known for the high antioxidant activity of its berries used as dietary supplements. Little is known about the biological activity and the composition of its vegetative organs. The objective of this study was to investigate the antioxidant activity of root and leaflet extracts of Euterpe oleracea (E. oleracea) and characterize their phytochemicals. E. oleracea roots and leaflets extracts were screened in different chemical antioxidant assays (DPPH-2,2-diphenyl-1-picrylhydrazyl, FRAP-ferric feducing antioxidant power, and ORAC-oxygen radical absorbance capacity), in a DNA nicking assay and in a cellular antioxidant activity assay. Their polyphenolic profiles were determined by UV and LC-MS/MS. E. oleracea leaflets had higher antioxidant activity than E. oleracea berries, and leaflets of Oenocarpus bacaba and Oenocarpus bataua, as well as similar antioxidant activity to green tea. E. oleracea leaflet extracts were more complex than root extracts, with fourteen compounds, including caffeoylquinic acids and C-glycosyl derivatives of apigenin and luteolin. In the roots, six caffeoylquinic and caffeoylshikimic acids were identified. Qualitative compositions of E. oleracea, Oenocarpus bacaba and Oenocarpus bataua leaflets were quite similar, whereas the quantitative compositions were quite different. These results provide new prospects for the valorization of roots and leaflets of E. oleracea in the pharmaceutical, food or cosmetic industry, as they are currently by-products of the açaí industry.
Assuntos
Antioxidantes/química , Euterpe/química , Extratos Vegetais/química , Antioxidantes/farmacologia , Apigenina/análise , Luteolina/análise , Oxirredução , Extratos Vegetais/farmacologia , Folhas de Planta/química , Raízes de Plantas/química , Ácido Quínico/análogos & derivados , Ácido Quínico/análiseRESUMO
Native palm trees fruit from the Amazonian rainforest, Oenocarpus bacaba and Oenocarpus bataua, are very often used in the diet of local communities, but the biological activities of their roots and leaflets remain poorly known. Total phenolic content (TPC) and antioxidant activity of root and leaflet extracts from Oenocarpus bacaba and Oenocarpus bataua were assessed by using different chemical assays, the oxygèn radical absorbance capacity (ORAC), the 2,2-diphenyl-l-picrylhydrazyl (DPPH) free radical-scavenging capacity and the ferric-reducing ability of plasma (FRAP). Cellular antioxidant activity and cytotoxicity were also measured in Normal Human Dermal Fibroblasts. The polyphenolic composition of Oenocarpus extracts was investigated by LC-MS(n). Oenocarpus leaflet extracts were more antioxidant than root extracts, being at least as potent as Euterpe oleracea berries known as superfruit. Oenocarpus root extracts were characterized by hydroxycinnamic acids (caffeoylquinic and caffeoylshikimic acids), while leaflet extracts contained mainly caffeoylquinic acids and C-glycosyl flavones. These results suggest that leaflets of both Oenocarpus species could be valorized as a new non-cytotoxic source of antioxidants from Amazonia, containing hydroxycinnamic acids and flavonoids, in the pharmaceutical, cosmetic or agri-food industry.