Planejamento e síntese de derivados triazólicos de biofenol como candidatos a novos fármacos e agroquímicos
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2019-02-25
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Universidade Federal de Viçosa
Resumo
O presente trabalho propôs uma rota sintética simples para análogos triazólicos do Tirosol, bi- ofenol encontrado no azeite de oliva e cujo amplo espectro de bioatividades tem sido alvo de muitos estudos. Os 1,2,3-triazóis, formados a partir da cicloadição 1,3-dipolar, têm sido ampla- mente utilizados nas últimas décadas, seja como grupo farmacofórico, seja como espaçador, podendo ser sintetizados a partir da química click. A modificação estrutural de compostos cuja atividade biológica já seja conhecida é uma estratégia importante na busca de novas moléculas sintéticas que sejam bioativas. Antes de iniciar a síntese dos análogos procedeu-se o planeja- mento racional das estruturas através do conceito de hibridação molecular e do cálculo dos parâmetros de drug-likeness e agrochemical-likeness. Foram obtidos 15 derivados inéditos do Tirosol, devidamente caracterizados pelas técnicas de RMN de 1 H e 13 C. Os compostos da série foram posteriormente avaliados como inibidores da enzima acetilcolinesterase (Electrophorus electricus). O estudo da inibição da acetilcolinesterase é importante para o desenvolvimento de novos fármacos capazes de controlar o Alzheimer, assim como para o desenvolvimento de novos inseticidas. Das moléculas avaliadas, os melhores derivados apresentaram inibições iguais a 24,8; 55,1; 32,1; 30,5 e 67,8%, sendo a maior inibição para o composto 7-({1-[2-(4- hidroxifenil)etil]-1H-1,2,3-triazol-4-il}metoxi)-4-metil-2H-cromen-2-ona (GMB14). Todas as estruturas foram posteriormente submetidas a docking molecular contra a acetilcolinesterase (Torpedo californica). Todos os ligantes interagiram com o sítio da enzima, corroborando para o estudo cinético com composto GMB14, que sugeriu inibição competitiva. O derivado GMB14, composto de maior atividade tanto experimentalmente quanto na simulação, interagiu com 47% dos aminoácidos do sítio ativo, alguns deles de regiões importantes para o combate do desenvolvimento da doença de Alzheimer. Os resultados apontam que os compostos desenvolvidos no presente trabalho podem ser usados como protótipos para desenvolvimento de novos inibidores da acetilcolinesterase. Palavras-chave: Tirosol; 1,2,3-triazóis; química click; drug-likeness; agrochemical-likeness; síntese racional; acetilcolinesterase; docking; mal de Alzheimer; inseticidas.
The present work proposed a simple synthetic route for triazolic analogues of Tyrosol, a bio- phenol found in olive oil and whose wide range of bioactivities has been the target of many studies. 1,β,γ-triazoles, formed from 1,γ-dipolar cycloaddition, have been widely used in the last decades, either as a pharmacophoric group or as a spacer, and can be synthesized from click chemistry. Structural modification (simplification or insertion of new groups) of compounds whose biological activity is already known is an important strategy in the search for new bio- active synthetic molecules. Before starting the synthesis of the analogues, the rational planning of the structures was carried out through the concept of molecular hybridization and the calcu- lation of the parameters of drug-likeness and agrochemical-likeness. We obtained 15 novel Ty- rosol derivatives, duly characterized by 1 H and 1γ C NMR techniques. The compounds of the series were later evaluated as inhibitors of the enzyme acetylcholinesterase (Electrophorus elec- tricus). The study of inhibition of acetylcholinesterase is important for the development of new drugs capable of controlling Alzheimer's disease, as well as for the development of new insec- ticides. Of the molecules evaluated, the best derivatives showed inhibitions equal to β4.8, 55.1, γβ.1, γ0.5 and 67.8%, with the highest inhibition for 7-({1-[β-(4-hydroxyphenyl)ethyl]-1H- 1,β,γ-triazol-4-yl}methoxy)-4-methyl-βH-chromen-β-one (GMB14). All structures were sub- sequently subjected to molecular docking against acetylcholinesterase (Torpedo californica). All ligands interacted with the enzyme site, corroborating for the kinetic study with compound GMB14, which suggested competitive inhibition. The GMB14 derivative, which has the high- est activity both experimentally and in the simulation, interacted with 47% of the active site amino acids, some of them important in the fight against the development of Alzheimer's dis- ease. The results indicate that the compounds developed in the present work can be used as prototypes for the development of new acetylcholinesterase inhibitors. Keywords: Tyrosol; 1,β,γ-triazoles; click chemistry; drug-likeness; agrochemical-likeness; ra- tional synthesis; acetylcholinesterase; docking; Alzheimer’s disease; insecticides.
The present work proposed a simple synthetic route for triazolic analogues of Tyrosol, a bio- phenol found in olive oil and whose wide range of bioactivities has been the target of many studies. 1,β,γ-triazoles, formed from 1,γ-dipolar cycloaddition, have been widely used in the last decades, either as a pharmacophoric group or as a spacer, and can be synthesized from click chemistry. Structural modification (simplification or insertion of new groups) of compounds whose biological activity is already known is an important strategy in the search for new bio- active synthetic molecules. Before starting the synthesis of the analogues, the rational planning of the structures was carried out through the concept of molecular hybridization and the calcu- lation of the parameters of drug-likeness and agrochemical-likeness. We obtained 15 novel Ty- rosol derivatives, duly characterized by 1 H and 1γ C NMR techniques. The compounds of the series were later evaluated as inhibitors of the enzyme acetylcholinesterase (Electrophorus elec- tricus). The study of inhibition of acetylcholinesterase is important for the development of new drugs capable of controlling Alzheimer's disease, as well as for the development of new insec- ticides. Of the molecules evaluated, the best derivatives showed inhibitions equal to β4.8, 55.1, γβ.1, γ0.5 and 67.8%, with the highest inhibition for 7-({1-[β-(4-hydroxyphenyl)ethyl]-1H- 1,β,γ-triazol-4-yl}methoxy)-4-methyl-βH-chromen-β-one (GMB14). All structures were sub- sequently subjected to molecular docking against acetylcholinesterase (Torpedo californica). All ligands interacted with the enzyme site, corroborating for the kinetic study with compound GMB14, which suggested competitive inhibition. The GMB14 derivative, which has the high- est activity both experimentally and in the simulation, interacted with 47% of the active site amino acids, some of them important in the fight against the development of Alzheimer's dis- ease. The results indicate that the compounds developed in the present work can be used as prototypes for the development of new acetylcholinesterase inhibitors. Keywords: Tyrosol; 1,β,γ-triazoles; click chemistry; drug-likeness; agrochemical-likeness; ra- tional synthesis; acetylcholinesterase; docking; Alzheimer’s disease; insecticides.
Descrição
Palavras-chave
Tirosol, 1,2,3-triazóis, Química, Drogas, Produtos químicos agrícolas, Tirosol - Síntese, Acetilcolinesterase, Alzheimer, Doença de, Inseticidas
Citação
BOUSADA, Guilherme Mateus. Planejamento e síntese de derivados triazólicos de biofenol como candidatos a novos fármacos e agroquímicos. 2019. 236 f. Dissertação (Mestrado em Agroquímica) - Universidade Federal de Viçosa, Viçosa. 2019.