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

CÂMARA, VIKTOR S.; BISCUSSI, BRUNELLA; SOARES, ANA JULIA; GUEDES, ISABELLA A.; DARDENNE, LAURENT; MURRAY, ANA PAULA; ZIMMER, ALINE R.; RUARO, THAÍS C.; CESCHI, MARCO A.

Virtual

Congreso; 44ª Reunião Anual da Sociedade Brasileira de Química; 2021

Sociedad Brasilera de Química

In the brain of patients with chronic Alzheimer’s Disease (AD), the butyrylcholinesterase (BuChE) levels rise while the acetylcholinesterase (AChE) levels decrease.1 Therefore, development of new selective BuChE inhibitors is of vital importance.2 In this work, a series of bis(n)-lophine analogues was designed to have two lophine derivatives connected by a methylene chain. The bis(n)-lophine analogues were synthesized through one-pot four component reaction between pyridinecarboxaldehydes, 1,nalkanediamines, 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 inhibition was found to be highly selective to BuChE since none of the bis(n)-lophine analogues were active against AChE, at the tested concentrations. The compounds displayed potent inhibitory activity against BuChE at a micromolar and sub-micromolar range (IC50 32.25–0.03 µM). The enzyme kinetic and docking studies suggest that the compounds act as a dual binding site inhibitors, binding into the bottom of the gorge and in the peripheral anionic site (PAS) of BuChE cavity. The bis(n)-lophine analogues were evaluated for their cytotoxicity against cellular models of VERO (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines, which are widely used as experimental models for seeking information about nephrotoxicity, hepatotoxicity, and neurotoxicity, respectively. The compounds tested showed no or slightly cytotoxic effects in all cellular models.