RESUMO
Praziquantel (PZQ), a broad spectrum anthelmintic drug, cannot be found in acceptable dosage forms for elderly patients, paediatric patients, and for veterinary use. In fact, very little has been done up to now in the formulation of liquid dosage forms, being they always formulated for parenteral administration. To beat this important challenge, it was accomplished a comprehensive analysis of the influence of two elementary physicochemical aspects, i.e. surface thermodynamic and electrokinetic properties, on the colloidal stability of PZQ nanosuspensions. The hydrophobic character of the drug, intensely determining the flocculation curves, was confirmed by the thermodynamic characterization. The electrophoretic characterization, in combination with the sedimentation and relative absorbance versus time curves, highlighted that the electrical double layer thickness and the surface charge can play an essential role in the stability of the pharmaceutical colloid. Finally, it was demonstrated that controlling the pH values and the incorporation of electrolytes can help in formulating PZQ aqueous nanosuspensions with appropriate stability and redispersibility behaviours for pharmaceutical use.
Assuntos
Anti-Helmínticos/síntese química , Composição de Medicamentos/métodos , Nanosferas/química , Praziquantel/síntese química , Anti-Helmínticos/farmacocinética , Química Farmacêutica/métodos , Eletrólitos/síntese química , Eletrólitos/farmacocinética , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Nanosferas/metabolismo , Praziquantel/farmacocinética , Água/química , Água/metabolismoRESUMO
The mechanochemical preparation of solid compositions of praziquantel with plant saponin (glycyrrhizic acid disodium salt) is described. The study of a number of physicochemical parameters showed that dissolving solid compositions in water is accompanied by the inclusion of praziquantel molecules into micelles, which are formed in the solution of the glycyrrhizic acid disodium salt. Using the opisthorchiasis model caused by Opisthorchis felineus, we found a 4- to 11-fold increase in the anthelmintic activity of praziquantel in the composition as compared to the official praziquantel. According to the pharmacokinetic data, the use of the composition increased the bioavailability of praziquantel 3 times.
Assuntos
Antiplatelmínticos/síntese química , Antiplatelmínticos/farmacologia , Ácido Glicirrízico/química , Fenômenos Mecânicos , Opistorquíase/tratamento farmacológico , Praziquantel/síntese química , Praziquantel/farmacologia , Animais , Antiplatelmínticos/farmacocinética , Antiplatelmínticos/uso terapêutico , Disponibilidade Biológica , Fenômenos Químicos , Técnicas de Química Sintética , Cricetinae , Praziquantel/farmacocinética , Praziquantel/uso terapêuticoAssuntos
Acesso à Informação , Pesquisa Biomédica/métodos , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Disseminação de Informação , Doenças Negligenciadas/tratamento farmacológico , Medicina Tropical/métodos , Pesquisa Biomédica/economia , Descoberta de Drogas/economia , Indústria Farmacêutica/economia , Humanos , Propriedade Intelectual , Doenças Negligenciadas/economia , Praziquantel/síntese química , Praziquantel/química , Esquistossomose/tratamento farmacológico , Fatores de Tempo , Medicina Tropical/economiaRESUMO
An organometallic derivative of praziquantel was studied directly in worms by using inductively coupled plasma-mass spectrometry (ICP-MS) for quantification and synchrotron-based imaging. X-ray fluorescence (XRF) and IR absorption spectromicroscopy were used for the first time in combination to directly locate this organometallic drug candidate in schistosomes. The detection of both CO (IR) and Cr (XRF) signatures proved that the Cr(CO)3 core remained intact in the worms. Images showed a preferential accumulation at the worm's tegument, consistent with a possible targeting of the calcium channel but not excluding other biological targets inside the worm.
Assuntos
Praziquantel/química , Schistosoma mansoni/química , Animais , Cromo/química , Espectrometria de Massas , Microscopia , Imagem Óptica , Praziquantel/síntese química , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/metabolismo , Espectrofotometria Infravermelho , Estereoisomerismo , Espectroscopia por Absorção de Raios XRESUMO
A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably, worm reduction rate of R-3 was 60.0% at a single oral dose of 200mg/kg against juvenile stage of Schistosoma japonicum. The target compounds displayed in vivo antischistosomal activity against both Schistosoma japonicum and Schistosoma mansoni. Furthermore, all R-isomers displayed stronger antischistosomal activity than S-isomers in vivo, indicating R-isomers were the active enantiomers, while S-isomers were less active ones. This structure activity relationship (SAR) could have important implications in further drug development for schistosomiasis.
Assuntos
Praziquantel/análogos & derivados , Praziquantel/farmacologia , Schistosoma japonicum/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Estrutura Molecular , Praziquantel/síntese química , Praziquantel/química , Schistosoma japonicum/crescimento & desenvolvimento , Schistosoma mansoni/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A series of NO-donor praziquantel hybrid compounds was obtained by combining praziquantel (PZQ) and furoxan moieties in a single entity. NO-donor properties of the furoxan derivatives were evaluated by detecting nitrite after incubation of the products in 7.4 pH buffered solution in the presence of L-cysteine. Structurally-related furazans, devoid of NO release capacity, were also synthesized for control purposes. All products were studied for their ability to inhibit recombinant Schistosoma mansoni thioredoxin glutathione reductase (TGR). Mobility and death of adult Schistosoma mansoni worms cultured in the presence of the products were evaluated versus PZQ. Analysis of the results showed that some products were endowed with both PZQ and NO-dependent antiparasitic properties. Compounds 6, 7, 18, and 24 emerged as the most interesting balanced hybrids, worthy of additional study on PZQ-resistant parasites.
Assuntos
Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Doadores de Óxido Nítrico/química , Oxidiazóis/química , Praziquantel/farmacologia , Pirazinas/química , Schistosoma mansoni/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Estrutura Molecular , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/metabolismo , Óxido Nítrico/química , Praziquantel/síntese química , Praziquantel/química , Schistosoma mansoni/enzimologia , Schistosoma mansoni/metabolismo , Relação Estrutura-AtividadeRESUMO
Schistosomiasis is a highly prevalent neglected tropical disease caused by blood-dwelling helminths of the genus Schistosoma. Praziquantel (PZQ) is the only drug available widely for the treatment of this disease and is administered in racemic form, even though only the (R)-isomer has significant anthelmintic activity. Progress towards the development of a second generation of anthelmintics is hampered by a lack of understanding of the mechanism of action of PZQ. In this Letter, we report an efficient protocol for the small-scale separation of enantiomers of 2 (hydrolyzed PZQ) using supercritical fluid chromatography (SFC). The enantiopure 2 was then used to develop several molecular probes, which can potentially be used to help identify the protein target of PZQ and study its mode of action.
Assuntos
Anti-Helmínticos/farmacologia , Desenho de Fármacos , Sondas Moleculares/síntese química , Sondas Moleculares/farmacologia , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/metabolismo , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/química , Cromatografia com Fluido Supercrítico , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Masculino , Modelos Moleculares , Sondas Moleculares/química , Estrutura Molecular , Terapia de Alvo Molecular , Praziquantel/síntese química , Praziquantel/química , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Estereoisomerismo , Especificidade por SubstratoRESUMO
The synthesis and structure-activity relationship (SAR) studies of praziquantel derivatives with activity against adult Schistosoma japonicum are described. Several of them showed better worm killing activity than praziquantel and could serve as leads for further optimization.
Assuntos
Praziquantel/síntese química , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Relação Estrutura-Atividade , Animais , Estrutura Molecular , Praziquantel/análogos & derivados , Praziquantel/farmacologia , Schistosoma japonicum/patogenicidade , Esquistossomose/parasitologia , Esquistossomicidas/administração & dosagemRESUMO
Schistosomiasis is one of the most burdensome of the neglected tropical diseases. Praziquantel is a recommended drug for treatment against all forms of schistosomiasis. To investigate the interaction between praziquantel and Schistosoma japonicum cercariae, two praziquantel derivatives (PZQ-2 and PZQ-3) and one praziquantel fluorescent derivative (PZQ-5) have been synthesized and characterized using nuclear magnetic resonance spectroscopy (NMR) and MS spectra. The cytotoxicity of PZQ-2, PZQ-3 and PZQ-5 was measured by performing the methyl thiazolyl tetrazolium (MTT) assay. The cell viability for them shows that the three compounds exhibit low cytotoxicity to HeLa cells. Cell imaging experiments demonstrate that PZQ-5 is biocompatible and cell-permeable, which indicates that PZQ-5 is suitable for studying their interaction. Confocal fluorescence microscopy revealed that PZQ-5 is mainly located at the cercarial tegument, which leads to the death of cercariae with the increase in time.
Assuntos
Cercárias/efeitos dos fármacos , Fluorescência , Praziquantel/farmacologia , Schistosoma japonicum/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cercárias/citologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Praziquantel/síntese química , Praziquantel/química , Schistosoma japonicum/citologia , Relação Estrutura-AtividadeRESUMO
A removable protecting group has been identified that allows the products of widely-used cross dehydrogenative couplings to be synthetically elaborated. The method can be used with enantiopure amines with no loss of enantiomeric excess. The methodology is exemplified by a new synthesis of enantiopure praziquantel, the drug used in the treatment of millions of people suffering from the neglected tropical disease, schistosomiasis.
Assuntos
Aminas/química , Anti-Helmínticos/síntese química , Praziquantel/síntese química , Anti-Helmínticos/química , Hidrogenação , Estrutura Molecular , Praziquantel/química , EstereoisomerismoRESUMO
The design, synthesis, and biological evaluation of 18 ferrocenyl derivatives (4A-12A and 4B-12B) of the most well-known drug against schistosomiasis, namely praziquantel (PZQ), are reported. These compounds, which have been all isolated as racemates, were unambiguously characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis as well as by X-ray crystallography for 4A, 5A, and 7A. Cytotoxicity studies revealed that the complexes were moderately toxic toward a cervical cancer cell line (HeLa) and, importantly, significantly less active toward a noncancerous cell line (MRC-5). The in vitro anthelmintic activity of the 18 ferrocenyl PZQ derivatives was tested against adult Schistosoma mansoni, and values in the micromolar range (26-68 µM) were determined for the four most active compounds. It was also demonstrated using two compounds of the series as models (8A and 8B) that the complexes were stable when incubated for 24 h at 37 °C in human plasma.
Assuntos
Compostos Ferrosos/síntese química , Praziquantel/análogos & derivados , Praziquantel/síntese química , Esquistossomicidas/síntese química , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Compostos Ferrosos/farmacologia , Humanos , Metalocenos , Modelos Moleculares , Estrutura Molecular , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An efficient synthesis of antischistosomal drug praziquantel and analogues was achieved and the synthetic route designed was to afford structurally diverse analogues for better structure-activity relationship understanding. Total of nineteen PZQ analogues with structural variations at amide, piperazine and aromatic moieties have been synthesized and fully characterized. Among all the new analogues tested for antischistosomal activity, one dimethoxy tetrahydroisoquinoline analogue and two tetrahydro-ß-carboline analogues exhibited moderate activity against adult Schistosoma mansoni. Tetrahydro-ß-carboline analogues showed moderate activity whereas the presence of p-trifluoromethylbenzoyl and p-toluenesulphonyl moieties resulted in complete suppression of antischistosomal activity.
Assuntos
Praziquantel/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Esquistossomicidas/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Estrutura Molecular , Praziquantel/síntese química , Praziquantel/química , Esquistossomicidas/síntese química , Esquistossomicidas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A praziquantel analog 10-hydroxy praziquantel and eight praziquantel/peroxide conjugates were synthesized. The biological activity of these compounds was evaluated against juvenile and adult stages of Schistosoma japonicum. Unlike praziquantel, 10-hydroxy praziquantel exhibits activity against both juvenile and adult Schistosoma japonicumin. All hybrid compounds displayed modest to significant worm killing activity. The present study has important significance for the development of hybrid antischistosomal drugs.
Assuntos
Praziquantel/farmacologia , Schistosoma japonicum/efeitos dos fármacos , Esquistossomose Japônica/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacologia , Animais , Humanos , Camundongos , Estrutura Molecular , Praziquantel/síntese química , Praziquantel/química , Esquistossomicidas/químicaRESUMO
Schistosomiasis, a high volume neglected tropical disease affecting more than 200 million people worldwide, can only be effectively treated by the tetrahydroisoquinoline drug praziquantel (PZQ). Herein, we describe an efficient approach to access PZQ derivatives by the Ugi 4-component reaction followed by the Pictet-Spengler reaction in a two-step, one-pot procedure. 30 novel PZQ derivatives are described based on the Ugi 4-component reaction and an X-ray structure of a novel derivative revealing different conformation compared with PZQ is discussed. Several analogues comparable in activity to the drug PZQ have been identified based on an in vitro Schistosoma mansoni worm viability assay.
Assuntos
Anti-Helmínticos/química , Anti-Helmínticos/farmacologia , Praziquantel/química , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Animais , Anti-Helmínticos/síntese química , Técnicas de Química Sintética/métodos , Cricetinae/parasitologia , Cristalografia por Raios X , Humanos , Modelos Moleculares , Praziquantel/síntese química , Esquistossomose/tratamento farmacológico , Esquistossomose mansoni/tratamento farmacológicoRESUMO
Schistosomiasis is a widespread tropical parasitic disease, currently treated with Praziquantel, whose precise molecular target is actually unknown. Several other drugs are known to kill the schistosomes in vivo and in vitro, but these are seldom employed because of toxicity, high cost, complex administration or other reasons. The improvement of known drugs or the development of entirely new ones is a desirable goal, in view of the fact that strains of Schistosoma mansoni with reduced sensitivity to Praziquantel have appeared. In this review, we tried to collect the information available on known or putative macromolecular targets of schistosomicidal drugs; thus we focused on the biochemistry of the parasite, rather than the clinical properties of the drugs. The rationale of this approach is that drug design may become realistic if the mechanism of action of each known drug were known at atomic detail, ideally as the 3D structure of each drug in complex with its target. Important macromolecular targets of known drugs reviewed below are: Thioredoxin Glutathione Reductase; Cyclophilin; Acetyl Cholinesterase; Proteases and Purine Nucleoside Phosphorylase. Moreover, a few enzymes of the parasite are known, or thought, to be "druggable", and therefore interesting, even though no specific drugs are available as yet: examples of such enzymes are Glutathione Peroxidase and Peroxiredoxins.
Assuntos
Auranofina/farmacologia , Inibidores Enzimáticos/farmacologia , Terapia de Alvo Molecular , Praziquantel/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Auranofina/síntese química , Auranofina/uso terapêutico , Cristalografia por Raios X , Ciclofilinas/antagonistas & inibidores , Ciclofilinas/química , Ciclofilinas/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Peroxidase/química , Glutationa Peroxidase/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Complexos Multienzimáticos/antagonistas & inibidores , Complexos Multienzimáticos/química , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/antagonistas & inibidores , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/metabolismo , Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Peroxirredoxinas/antagonistas & inibidores , Peroxirredoxinas/química , Peroxirredoxinas/metabolismo , Praziquantel/síntese química , Praziquantel/uso terapêutico , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/química , Purina-Núcleosídeo Fosforilase/metabolismo , Schistosoma mansoni/enzimologia , Esquistossomose/parasitologia , Esquistossomicidas/síntese química , Esquistossomicidas/uso terapêuticoAssuntos
Praziquantel/síntese química , Praziquantel/farmacologia , Esquistossomose/tratamento farmacológico , Esquistossomicidas/síntese química , Esquistossomicidas/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Praziquantel/química , Praziquantel/economia , Esquistossomicidas/química , Esquistossomicidas/economiaAssuntos
Anti-Helmínticos/química , Praziquantel/química , Esquistossomose/tratamento farmacológico , Animais , Anti-Helmínticos/síntese química , Anti-Helmínticos/uso terapêutico , Glutationa Transferase/química , Praziquantel/síntese química , Praziquantel/uso terapêutico , Esquistossomose/epidemiologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Bicyclization of peptide acetals via nucleophilic attack of a phenyl group on an endocyclic acyliminium ion 4 was explored as a route to novel amino acid derived heterocycles and peptidomimetic scaffolds. In the presence of protic acid, bridged structures such as 6 are formed readily from phenylalanine derivatives, but the fused-ring analogues 5 could not be obtained in good yield. In contrast, radical cyclization of the bromophenyl dihydropyrazinone 7 provides an effective alternative for the synthesis of 5 (n = 0, 1, 2). Additional versatility in this process was demonstrated by efficient synthesis of a different fused ring system, represented by the antihelmintic praziquantel, 8.
Assuntos
Aminoácidos/química , Técnicas de Química Combinatória , Peptídeos/química , Acetais , Catálise , Ciclização , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , Preparações Farmacêuticas , Praziquantel/síntese química , Pirazinas/síntese química , Pirazinas/químicaRESUMO
As a continuation for our previous approaches to establish structure-antischistosomal activity relationship (SAR) among some new rationally synthesized analogues of praziquantel, herein a new C-4 and C-12 dithione mimic of the drug namely, 2-cyclohexylthiocarbonyl (1, 2, 3, 6, 7, 11b) hexahydro-4H-pyrazino[2-la]isoquinoline-4-thione (II) was synthesized and antischistosomally investigated (mice infected with S. masoni cercariae). Further, some significant biochemical and toxicological parameters for both the control and the dithione II treated mice, particularly the total serum and liver proteins, liver enzymes, serum total lipids, cholesterol, triglycerides, albumin, globulins and creatinine, were assayed. The determined induced amino acid profile of liver protein hydrolysate could indicate a close similarity of the working biological mechanism for both I and II. Comparable to praziquantel, the dithione II was found, still promisingly antischistosomally active (approximately 70% of I, collective average activity, based on 500 mg II/kg mouse body weight). Equally, generally tolerant toxicity parameters for liver and kidney functions could be attributed. Due to the still absence of quasi-potent praziquantel candidates since its discovery (1975), the dithione II could be considered as an interesting anthelminthic candidate susceptible for further profound studies and structure modulations. In this context, some perspectives were also suggested.
Assuntos
Isoquinolinas/síntese química , Praziquantel/análogos & derivados , Praziquantel/síntese química , Pirazinas/síntese química , Esquistossomicidas/síntese química , Animais , Cromatografia em Camada Fina , Isoquinolinas/farmacologia , Camundongos , Praziquantel/farmacologia , Pirazinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/farmacologiaRESUMO
2-Palmitoyl[1,2,3,6,7,11b]hexahydro-4H-pyrazino[2-la]isoquinoline-4-one [III] a highly lipophilic analogue of the universal antihelminthic PRAZIQUANTEL [I] was rationally multi-stepwise synthesized and antischistosomally and biochemically screened. The 2-palmitoyl conjugation was hypothesized to be an antischistosomal adjuvant (Tween 40 mimicry), to the reported crucial pyrazino-isoquinoline moiety. On a constant weight doses bases of I and III (500 mg/kg mouse body weight), the activity of III was found to be approximately 70% of I (mice infected with S. mansoni cercariae) and with satisfactory toxicological and biochemical profile (mice liver and kidney functions). Equivalent molar weight assay (M 1:1.4 for I and III, respectively), which could further plead in favour of the potency of III, was not yet tested. The analogue III, which favourable incorporates the human metabolically and physiologically compatible, palmitic acid segment, seems to be an antischistosomally promising candidate for more integrated studies.