RESUMO
The current standard of care for cutaneous leishmaniasis (CL) is organic antimonial compounds, but the administration of these compounds is complicated by a low therapeutic - toxic index, as well as parenteral administration. Thus, there is an urgent need for the development of new and inexpensive therapies for the treatment of CL. In this study, we evaluate the activity of the triphenylmethane (TPM) class of compounds against three species of Leishmania which are pathogenic in humans. The TPM have a history of safe use in humans, dating back to the use of the original member of this class, gentian violet (GV), from the early 20(th) century. Initially, the in vitro efficacy against Leishmania (Viannia) braziliensis, L. (Leishmania) amazonensis and L. (L.) major of 9 newly synthesized TPM, in addition to GV, was tested. Inhibitory concentrations (IC) IC(50) of 0.025 to 0.84 µM had been found in promastigotes in vitro assays. The four most effective compounds were then tested in amastigote intracellular assays, resulting in IC(50) of 0.10 to 1.59 µM. A high degree of selectivity of antiparasitic activity over toxicity to mammalian cells was observed. Afterwards, GV and TPM 6 were tested in a topical formulation in mice infected with L. (L.) amazonensis leading to elimination of parasite burdens at the site of lesion/infection. These results demonstrated that TPM present significant anti-leishmanial activities and provide a rationale for human clinical trials of GV and other TPM. TPM are inexpensive and safe, thus using them for treatment of CL may have a major impact on public health.
Assuntos
Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Compostos de Tritil/farmacologia , Compostos de Tritil/uso terapêutico , Animais , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/parasitologia , Leishmania/citologia , Leishmania/crescimento & desenvolvimento , Leishmania braziliensis/efeitos dos fármacos , Estágios do Ciclo de Vida/efeitos dos fármacos , Camundongos , Peso Molecular , Compostos de Tritil/químicaRESUMO
In this study, we investigated the effects of 2,2'-dithienyl diselenide (DTDS), an organoselenium compound, against seizures induced by kainic acid (KA) in rats. Rats were pretreated with DTDS (50 or 100 mg/kg) by oral route 1 h before KA injection (10 mg/kg, intraperitoneal). Our results showed that DTDS (100 mg/kg) was effective in increasing latency for the onset of the first clonic seizure episode induced by KA, as well as in decreasing the appearance of seizures and the Racine's score. DTDS also caused a decrease in the excitatory electroencephalographic (EEG) changes, resulting from KA exposure in hippocampus and cerebral cortex of rats. Besides, elevated reactive species (RS) and carbonyl protein levels and Na(+), K(+)-ATPase activity in hippocampus of rats treated with KA were ameliorated by DTDS (50 and 100 mg/kg). Lastly, as evidenced by Cresyl-Violet stain, DTDS (100 mg/kg) elicited a protective effect against KA-induced neurodegeneration in rat hippocampus 7 days after KA injection. In conclusion, the present study showed that DTDS attenuated KA-induced status epilepticus in rats and the subsequent hippocampal damage.
Assuntos
Hipocampo/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Compostos Organosselênicos/uso terapêutico , Tiofenos/uso terapêutico , Timidina/análogos & derivados , Compostos de Tritil/uso terapêutico , Análise de Variância , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroencefalografia , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ácido Caínico/toxicidade , Masculino , Fármacos Neuroprotetores/química , Síndromes Neurotóxicas/complicações , Síndromes Neurotóxicas/etiologia , Neurotoxinas/toxicidade , Compostos Organosselênicos/química , Estresse Oxidativo/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Convulsões/etiologia , Convulsões/prevenção & controle , ATPase Trocadora de Sódio-Potássio/metabolismo , Compostos de Sulfidrila/metabolismo , Tiofenos/química , Timidina/química , Timidina/uso terapêutico , Compostos de Tritil/químicaRESUMO
The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation) between the molecules of 5'-O-Tr-2'-deoxynucleosides in a process mediated by anhydrous sulfates of Cu(+2), Fe(+2), or Ni(+2) to yield mixtures of 3',5'-bis-O-Tr and 3'-O-Tr products. If phenylmethanol is present in a reaction medium, detritylation results with concomitant formation of phenylmethyl triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5'-O-TBDMS-2'-deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for the O-Tr and O-TBDMS groups.
Assuntos
Química Orgânica/métodos , Nucleosídeos/química , Siloxanas/química , Estirenos/química , Compostos de Tritil/química , Sulfato de Cálcio/química , Estrutura MolecularRESUMO
Selective inhibition of the intermediate-conductance Ca(2+)-activated K(+ )channel (IK (Ca)) by some clotrimazole analogs has been successfully modeled using topological charge indexes (TCI) and genetic neural networks (GNNs). A neural network monitoring scheme evidenced a highly non-linear dependence between the IK (Ca) blocking activity and TCI descriptors. Suitable subsets of descriptors were selected by means of genetic algorithm. Bayesian regularization was implemented in the network training function with the aim of assuring good generalization qualities to the predictors. GNNs were able to yield a reliable predictor that explained about 97% data variance with good predictive ability. On the contrary, the best multivariate linear equation with descriptors selected by linear genetic search, only explained about 60%. In spite of when using the descriptors from the linear equations to train neural networks yielded higher fitted models, such networks were very unstable and had relative low predictive ability. However, the best GNN BRANN 2 had a Q ( 2 ) of LOO of cross-validation equal to 0.901 and at the same time exhibited outstanding stability when calculating 80 randomly constructed training/test sets partitions. Our model suggested that structural fragments of size three and seven have relevant influence on the inhibitory potency of the studied IK (Ca) channel blockers. Furthermore, inhibitors were well distributed regarding its activity levels in a Kohonen self-organizing map (KSOM) built using the inputs of the best neural network predictor.