Expedient Microwave-Assisted Synthesis of Bis(n)-lophine Analogues as Selective Butyrylcholinesterase Inhibitors: Cytotoxicity Evaluation and Molecular Modelling

Journal of the Brazilian Chemical Society

article

Câmara, Viktor S.¹  Soares, Ana Julia¹  Biscussi, Brunella²  Murray, Ana Paula²  Guedes, Isabella A.³  Dardenne, Laurent E.³  Ruaro, Thaís C.⁴  Zimmer, Aline R.⁴  Ceschi, Marco A.¹ 

[1] Instituto de Química, Universidade Federal do Rio Grande do Sul, Campus do Vale;Departamento de Química, Instituto de Química del Sur, Universidad Nacional del Sur;Laboratório Nacional de Computação Científica;Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul

关键词: cholinesterase inhibitor;    butyrylcholinesterase;    bis(n)-lophine analogues;   

DOI  :  10.21577/0103-5053.20210018

学科分类：内科医学

来源: SciELO

【 摘 要 】

In the brain of patients with chronic Alzheimer’s disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, development of new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophine analogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions were performed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps for unsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of them inhibit AChE. All the compounds, except 7a , 7b and 7c , displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (half maximal inhibitory concentration (IC 50 ) 32.25-0.03 µM). The enzyme kinetic and docking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studies showed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6 astroglial cell lines.

【 授权许可】

CC BY