Combining the Pharmacophore Features of Coumarins and 1,4-Substituted 1,2,3-Triazoles to Design New Acetylcholinesterase Inhibitors: Fast and Easy Generation of 4-Methylcoumarins/1,2,3-triazoles Conjugates via Click Chemistry

Journal of the Brazilian Chemical Society

Universidade de São Paulo, Ribeirão Preto, Brazil¹  Andrade, Saulo¹  Garcia, Solange C.¹  Eifler-Lima, Vera L.¹  Merlo, Aloir A.¹  Piedade, Maristela¹  Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil¹  Vanzolini, Kenia L.¹  Centro Universitário Ritter dos Reis, Porto Alegre, Brazil¹  Torres, Fernando C.¹  Cass, Quezia B.¹  Holzschuh, Maribete¹  Gonçalves, Guilherme A.¹  Kawano, Daniel F.¹  Universidade Estadual de Campinas, Campinas, Brazil¹  Universidade Federal de São Carlos, São Carlos, Brazil¹  Gauer, Bruna¹  Poser, Gilsane L. von¹  Carvalho, Ivone¹ 

关键词:  Alzheimer's disease;    acetylcholinesterase;    coumarins;    click chemistry;   

DOI  :  10.5935/0103-5053.20160033

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Coumarins are a large class of compounds that display a range of interesting biological properties, being considered privileged structures because of the ability of their 2H-chromen-2-one nuclei to bind to multiple pharmacological targets. We hypothesized that the linkage of a second pharmacophore nucleus to the 2H-chromen-2-one core, the 1,2,3-triazole moiety, would entail more selective and pharmacologically active coumarins. Therefore, we describe the synthesis of fourteen 4-methylcoumarins/1,4-substituted 1,2,3-triazole conjugates, which were predicted by in silico methods to inhibit acetylcholinesterase (AChE) and proved to be moderate in vitro inhibitors of this enzyme. Molecular docking simulations suggest that the most active of these compounds has a putative binding mode similar to donepezil, both occupying the peripheral anionic site of AChE, which is associated with the secondary noncholinergic functions of the enzyme. This highlights the potential of this series for further optimization in the search of new coumarins for the treatment of Alzheimer's disease.

【 授权许可】

Unknown