Desenvolvimento de potenciais agentes leishmanicidas: benzotiazois inibidores de N-miristoiltransferase

• Ano de defesa: 2016
• Autor(a) principal: Junqueira, Luis Otavio [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo
• Palavras-chave em Português: Benzothiazoles; Thiazoles; Leishmanicidal; Neglected diseases; N-myristoyltranferase; Benzotiazóis; Tiazóis; Leishmanicidas; Doenças negligenciadas; N-miristoiltranferase
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3653222; http://repositorio.unifesp.br/handle/11600/46310

N-myristoyltransferase is an enzyme responsible for anchoring proteins to the plasma mem- brane through a cotranslational mechanism of lipidation of proteins in eukaryotes. Previous studies have shown the benzothiazolic nucleus as promising for the development of a new class of NMT in- hibitor compounds. In this study, two benzothiazolic analogs were synthetized and tested against Leishmania (Leishmania) amazonensis. The study began with the synthesis of 6-hidroxi- benzotiazolato de etila followed by the alkylation of the 6-hidroxi position of this intermediate with a consecutive reaction of said alkylated intermediate with 3-picolamina or benzilamina. The products obtained had good purity despite the lower yield. It was also proposed the synthesis of a thiazolic de- rivative which would allow the valuation of the influence from the benzothiazolic core flexibility over the leishmanicide biological activity. The compound derived from 3-picolylamine was sent, along with its synthetic intermediates, for biological activity, showing activity in the order of 21,75 µM. The bio- logical activity profile was attributed to the low lipophilicity of the product obtained after the addition of the picolylaminic groups to the structure. The biological analysis of the derivate obtained from the benzylamine might confirm this hypothesis since it is more lipophilic than the 3-picolilamine derivate. Still, the activity shown by the tested compound demonstrates how this class of benzoheterocycles compounds might be promising for the development of new drugs with leishmanicide activity. Theo- retical studies using molecular docking were conducted with LmNMT in the means of assessing the binding of the benzothiazolic compounds that were obtained to this enzyme. The results showed that the benzothiazolic compounds constitute a class of molecules with a potential for interaction with the LmNMT target. The synthesis of flexible thiazolic analogs and finishing up of biological tests consti- tute the perspectives of the present study.