Author | Lopes, João Paulo Bizarro | |
Author | Silva, Luana | |
Author | Franarin, Gabriela da Costa | |
Author | Ceschi, Marco Antonio | |
Author | Lüdtke, Diogo Seibert | |
Author | Dantas, Rafael Ferreira | |
Author | Salles, Cristiane Martins Cardoso de | |
Author | Silva Junior, Floriano Paes | |
Author | Senger, Mario Roberto | |
Author | Guedes, Isabella Alvim | |
Author | Dardenne, Laurent Emmanuel | |
Access date | 2019-02-18T15:59:07Z | |
Available date | 2019-02-18T15:59:07Z | |
Document date | 2018 | |
Citation | LOPES, João Paulo Bizarro et al. Design,synthesis,cholinesterasei nhibition and molecular modelling study of nove ltacrine hybrids with carbohydrate derivatives. Bioorganic & Medicinal Chemistry, v. 26, p. 5566-5577, Oct. 2018. | pt_BR |
ISSN | 0968-0896 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/31707 | |
Language | eng | pt_BR |
Publisher | Elsevier | pt_BR |
Rights | restricted access | pt_BR |
Subject in Portuguese | Tacrina | pt_BR |
Subject in Portuguese | Carboidrato | pt_BR |
Subject in Portuguese | Xilose | pt_BR |
Subject in Portuguese | Ribose | pt_BR |
Subject in Portuguese | Galactose | pt_BR |
Subject in Portuguese | Colinesterases | pt_BR |
Subject in Portuguese | Modelagem Molecular | pt_BR |
Subject in Portuguese | Alzheimer | pt_BR |
Title | Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives | pt_BR |
Type | Article | pt_BR |
DOI | 10.1016/j.bmc.2018.10.003 | |
Abstract | A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II. | pt_BR |
Affilliation | Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS, Brasil. | pt_BR |
Affilliation | Universidade Federal do Rio Grande do Sul. Instituto de Química. Porto Alegre, RS, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Rural do Rio de Janeiro. Instituto de Ciências Exatas. Seropédica, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica Experimental e Computacional de Fármacos. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Laboratório Nacional de Computação Científica. Petrópolis, RJ, Brasil. | pt_BR |
Affilliation | Laboratório Nacional de Computação Científica. Petrópolis, RJ, Brasil. | pt_BR |
Subject | Tacrine | pt_BR |
Subject | Carbohydrate | pt_BR |
Subject | Xylose | pt_BR |
Subject | Ribose | pt_BR |
Subject | Galactose | pt_BR |
Subject | Cholinesterases | pt_BR |
Subject | Molecular modeling | pt_BR |
Subject | Alzheimer | pt_BR |
Embargo date | 2022-01-01 | |