Design,synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives |
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Authors: | João Paulo Bizarro Lopes Luana Silva Gabriela da Costa Franarin Marco Antonio Ceschi Diogo Seibert Lüdtke Rafael Ferreira Dantas Cristiane Martins Cardoso de Salles Floriano Paes Silva-Jr Mario Roberto Senger Isabella Alvim Guedes Laurent Emmanuel Dardenne |
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Institution: | 1. Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Campus do Vale, 91501-970, Porto Alegre, RS, Brazil;2. Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil, 4365, 21040-360, Rio de Janeiro, RJ, Brazil;3. Instituto de Ciências Exatas, Universidade Federal Rural do Rio de Janeiro, BR 465, Km 7, Campus Universitário, 23890-000 Seropédica, RJ, Brazil;4. Laboratório Nacional De Computação Científica-LNCC, Av. Getúlio Vargas, 333, Petrópolis 25651-075, RJ, Brazil |
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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. |
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Keywords: | Tacrine Carbohydrate Xylose Ribose Galactose Cholinesterases Molecular modeling Alzheimer |
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