Síntese de pró-fármacos dendriméricos potencialmente antichagásicos e leishmanicidas derivados de hidroximetilnitrofural, 3-hidroxiflavona e quercetina / Synthesis of dendrimer prodrugs potentially antichagasic and antileishmanial derivatives from hydroxymethylnitrofurazone, 3-hydroxyflavone and quercetin

O Trypanosoma cruzi é o agente etiológico da tripanossomíase americana ou doença de Chagas. A infecção ocorre desde o sul dos EUA até o sul da Argentina e cerca de 20 milhões de pessoas da América Latina correm o risco de adquirir a doença. Já a leishmaniose é causada por aproximadamente 17 diferentes espécies de protozoários unicelulares pertencentes à família Trypanosomatidae. Aproximadamente 350 milhões de pessoas correm o risco de contrair a infecção e estimam-se que existam 12 milhões de pessoas infectadas. A quimioterapia para estas duas doenças negligenciadas é limitada e os fármacos disponíveis na terapêutica são tóxicos, com eficácia discutível, podem causar resitência e, ocasionalmente, a administração parenteral é necessária. Frente ao exposto, a pesquisa e desenvolvimento de novos fármacos é necessária. À vista de tais fatos e utilizando-se o método de modificação molecular latenciação, o objetivo deste trabalho é a síntese e caracterização de pró-fármacos dendriméricos de primeira geração de hidroximetilnitrofural, 3-hidroxiflavona e quercetina. O hidroximetilnitrofural tem mostrado atividade contra as formas amastigotas e tripomastigotas do T. cruzi in vitro e in vivo. Os flavonóides 3-hidroxiflavona e quercetina mostraram-se mais ativos que o padrão miltefosina em ensaios in vitro para leishmaniose. Já os dendrímeros são novas arquiteturas moleculares com estruturas nanoscópicas, extremamente organizadas e apresentam massa molecular definida. As aplicações incluem, por exemplo, a atuação como agentes transportadores de fármacos. Diversas metodologias sintéticas foram desenvolvidas na tentativa de se obter os pró-fármacos dendriméricos. Um das maiores dificuldades encontradas foi a purificação dos compostos sintetizados. Adicionalmente, foram realizados estudos de modelagem molecular para auxiliar a compreensão sobre a liberação das substâncias ativas da malha dendrimérica. Experimentos sobre hidrólise enzimática do pró-fármaco composto por...

Trypanosoma cruzi is the etiological agent of American trypanosomiasis or Chagas' disease. The infection occurs from the southern USA to southern Argentina and about 20 million people in Latin America are at risk of acquiring the disease. Leishmaniasis is caused by approximately 17 different species of unicellular protozoa belonging to the family Trypanosomatidae. Approximately 350 million people are at risk of acquiring the infection and it is estimated that there are 12 million people infected. Chemotherapy for these two neglected diseases is limited and the drugs available on therapy are toxic, with uncertain efficacy, may cause resistance and, occasionally, intravenous administration is required. Based on these facts, research and development for new drugs is needed. Considering that and using the method of molecular modification prodrug design, the purpose of this work is the synthesis and characterization of first generation dendrimer prodrug of hydroxymethylnitrofurazone (NFOH), quercetin and 3-hydroxyflavone. The NFOH has shown activity against amastigotes and trypomastigotes of T. cruzi, in vitro and in vivo. The flavonoids quercetin and 3-hydroxyflavone were more active than miltefosine in in vitro assays for leishmaniasis. Dendrimers are new molecular architectures with nanoscopic structures, extremely organized and it has defined molecular weight. The applications include, for instance, working as drugs carriers. A range of synthetic methodologies have been developed in an attempt to synthesize the dendrimers prodrugs. A major difficulty was the purification of the compounds. Additionally, molecular modeling studies were performed to assist understanding the release of active agents from dendrimers. Experiments concerning the enzymatic hydrolysis of the dendrimer prodrug composed by PAMAM (generation 1) and 3-hydroxyflavone were also made.

Quercetin glycosides in Psidium guajava L: leaves and determination of a spasmolytic principle

The traditional herbal remedy from Psidium guajava leaves had been medically proposed in mexico as effective treatment of acute diarrhea. A methanolic leaf extract was subjected to a bioassay-guided isolation of spasmolytic constituents. Six fractions were separated on a polyvinylpolypyrrolidine (PVPP) columm using a water methanol-gradient. The fraction containing flavonols inhibited peristalsis of guinea pig ileum in vitro. A trace of quercetin aglycone together with five glycosides was isolated from this active fraction and identified as quercentin 3-O-alpha-L-arabinoside (guajaravin); quercetin 3-O-ß-D-glucoside (isoquercetin); quercetin 3-O-ß-D-galactoside (hyperin); quercetin 3-O-ß-L-rhamnoside (quercitrin) and quercetin 3-O-gentobioside. Biological activity of each pure compound was studied in the same bioassay. Obtained results suggets that the spasmolytic activity of the Psidium guajava leaf remedy is mainly due to the aglycone quercetin, present in the leaf and in the extract mainly in the form of live flavonols, and whose effect is produced when these products are hydrolyzed by gastrointestinal fluid

Calcium-antagonist effect of quercetin and its relation with the spasmolytic properties of Psidium guajava L

The antidiarrheal properties of water ad methanolic extracts of Psidium guajava leaves have been demonstrated with anteriority and their spasmolytic effect was attributed to quercetin, a flavonoid conatined in this plant. The present paper reports the intestinal smooth muscle relaxation produced by quercetin on isolated guinea pig ileum previously contracted by a depolarizing KCl solution. Quercetin also inhibited intestinal contraction induced by different concentrations of calcium, shifting the contraction curve to the right showing a clear clacium-antagonistic efecct. Quercetin effect on ileal and aortic smooth muscles ar compared, the ileum being more sensitive to this flavonoid. The clacium antagonist property of quercetin is discussed and also its contribution to explain the spasmolytic effect of this popular herbal remedy