Expedient microwave-assisted synthesis of bis(n)-lophine analogues as selective butyrylcholinesterase inhibitors: cytotoxicity evaluation and molecular modelling.

VIKTOR SARAIVA CÂMARA; ANA JULIA SOARES; BISCUSSI, BRUNELLA; ANA PAULA MURRAY; ISABELLA A. GUEDES; LAURENT E. DARDENNE; THAÍS CARINE RUARO; ALINE RIGON ZIMMER; MARCO A. CESCHI

JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY

SOC BRASILEIRA QUIMICA

Lugar: San Pablo; Año: 2021 vol. 32 p. 1173 - 1185

0103-5053

In the brain of patients with chronic Alzheimer?s Disease (AD), the butyrylcholinesterase(BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease. Therefore, developmentof new selective BuChE inhibitors is of vital importance. Here we present a series of bis(n)-lophineanalogues, where two lophine derivatives are connected by a methylene chain. The bis(n)-lophineanalogues were synthesized through one-pot four component reaction betweenpyridinecarboxaldehydes, 1,n-alkanediamines, benzil, and ammonium acetate. The reactions wereperformed in a microwave reactor in one step for symmetrical bis(n)-lophines, and in two steps forunsymmetrical bis(n)-lophines. The compounds are strongly selective to BuChE, since none of theminhibit AChE. All the compounds, except 7a, 7b and 7c, displayed potent inhibitory activity againstBuChE at a micromolar and sub-micromolar range (IC50 32.25?0.03 μM). The enzyme kinetic anddocking studies suggests that the inhibitor act as a dual binding site inhibitor, binding into the bottomof the gorge and in the peripheral anionic site (PAS) of BuChE cavity. Furthermore, in vitro studiesshowed that compounds 5b and 12b had no cytotoxic effects in kidney Vero, hepatic HepG2 and C6astroglial cell lines.