Identification of dibenzyl imidazolidine and triazole acetamide derivatives through virtual screening targeting amyloid beta aggregation and neurotoxicity in PC12 cells

Aggregation and neurotoxicity of amyloid beta (A beta) protein is a hallmark characteristic of Alzheimer's disease (AD). In this study we compared the anti-aggregatory and neuroprotective effects of five synthetic compounds against A beta protein; four of which possessed a five membered heterocycle ring scaffold (two dibenzyl phenyl imidazolidines and two triazole sulfanyl acetamides) and one with a fused five membered heterocycle (benzoxazole) ring, selected thorough virtual screening from ZINC database. Molecular docking of their optimized structures was used to study A beta binding characteristics. As predicted from molecular docking, strong steric binding of imidazolidines and H-bonding of both triazoles to A beta were translated into anti A beta aggregation properties. Subsequent transmission electron microscopy (TEM) was used to assess their effects on A beta(1-42) fibril formation. Four compounds variably altered morphology of Ab fibrils from long, intertwined fibrils to short, loose structures. Thioflavin T assay of A beta fibrillisation kinetics demonstrated that one imidazolidine and both triazole compounds inhibited A beta aggregation. Rat pheochromocytoma (PC12) cells were exposed to A beta(1-42), alone and in combination with the heterocyclic compounds to assess neuroprotective effects. A beta(1-42)-evoked loss of neuronal cell viability was significantly attenuated in the presence of both imidazolidine compounds, while the triazole acetamides and benzoxazole compound were toxic to PC12 cells. These findings highlight the A beta anti-aggregative and neuroprotective propensity of a dibenzyl phenyl imidazolidine scaffold (Compound 1 and 2). While the triazole sulfanyl acetamide scaffold also possessed A beta anti-aggregation properties, they also demonstrated significant intrinsic neurotoxicity. Overall, the predictive efficacy of in silico methods enables the identification of novel imidazolidines that act both as inhibitors of A beta aggregation and neurotoxicity, and may provide a further platform for the development of novel Alzheimer's diseasemodifying pharmacotherapies. Crown Copyright (c) 2017 Published by Elsevier Masson SAS. All rights reserved.