Desreplicação molecular de espécies vegetais, simplificação e análise farmacocinética in vitro de análogos de licarina-a como protótipo de potenciais antiparasitários e antitumorais

• Ano de defesa: 2018
• Autor(a) principal: Morais, Thiago Rahal [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Piper; Licarin A; Pharmacokinetics; Cytotoxic activity; Antiparasitic activity; Licarina A; Farmacocinética; Atividade citotóxica; Atividade antiparasitária
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=7727045; https://repositorio.unifesp.br/handle/11600/53199

In the following work, the cytotoxic and antiparasitic activities were evaluated as well as the molecular dereplication (by HPLC and NMR) of the hexanic and methanolic extracts of different Piper plants (P. arboreum, P. solmnsianum, P. cernuum, P. gaudichaudianum, P. aduncum, P. umbellatum and P. regnellii). Among the extracts studied, those belonging to the species P. cernuum were selected for a biomonitoring chemical study, since the leaf and branch extracts presented cytotoxic and antiparasitic potential. From this process, three lignans (cubebin, hinokinin and kusunokinin) were isolated from the leaves, the latter two occurring for the first time in the species. From the branches was isolated and characterized the bornyl p-coumarate as bioactive compound, whose occurrence is being described for the first time in the species. In addition to these active compounds, two inactive sesquiterpenes were obtained (epi-dihydroagarofuran and 11-hydroxy-4,5-secoeudesman-4,5-dione), also described for the first time in the species. In addition, extracts from the leaves of P. regnellii were submitted to chromatographic fractionation biomonitored by the antiparasitary and cytotoxic activities evaluation from which the neolignan licarin A was isolated and identified. From this bioactive compound and aiming the establishment of SAR (six structures were prepared from methylation, acetylation, allylation, Claisen-like and iodocyclization reactions that were tested for their antiparasitic and cytotoxic activities. In advance of this study, simpler structures were planned with the aim of molecular optimization, maintaining the characteristics of the pharmacophore present in the licarin A derivatives (eugenol, isoeugenol, vanillin and vanillic alcohol) and meeting the initial parameters of pharmacokinetics (ADME), especially in the absorption aspect (A). Thus, in vitro models of permeability of the gastro-intestinal tract and blood-brain barrier (PAMPA-GIT / BBB) and tissue permeability of the intestinal membrane of CD-1 mice (ex vivo model) were performed using the Ussing method. The simpler analogues were easier to permeate the membranes of the various models due to the lower partition coefficient compared to the licarin A derivatives (log P ≥ 4), a major factor required in the development of new drugs. The 2-allyl derivative of licarin-A exhibited higher activity against T. cruzi trypomastigotes with EC50 = 5.0 μM. In contrast, the 2-allylated derivative of isoeugenol presented values of EC50 = 21.2 and 10.4 μM for trypomastigote and amastigote forms, respectively. We concluded that the 2-allyl-isoeugenol analogue maintained the cytotoxic characteristics for tumor and antiparasitic lines indicating the structural particularity and importance attributed to the phenolic and propenyl groups present, in addition to having greater effectiveness in the permeability which makes this compound a good prototype for future studies of new molecular optimization and in vivo assays.