title: Identification of dibenzyl imidazolidine and triazole acetamide derivatives through virtual screening targeting amyloid beta aggregation and neurotoxicity in PC12 cells.
abstract: Aggregation and neurotoxicity of amyloid β (Aβ) 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 Aβ 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 Aβ binding characteristics. As predicted from molecular docking, strong steric binding of imidazolidines and H-bonding of both triazoles to Aβ were translated into anti Aβ aggregation properties. Subsequent transmission electron microscopy (TEM) was used to assess their effects on Aβ1-42fibril formation. Four compounds variably altered morphology of Aβ fibrils from long, intertwined fibrils to short, loose structures. Thioflavin T assay of Aβ fibrillisation kinetics demonstrated that one imidazolidine and both triazole compounds inhibited Aβ aggregation. Rat pheochromocytoma (PC12) cells were exposed to Aβ1-42, alone and in combination with the heterocyclic compounds to assess neuroprotective effects. Aβ1-42-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 Aβ anti-aggregative and neuroprotective propensity of a dibenzyl phenyl imidazolidine scaffold (Compound 1 and 2). While the triazole sulfanyl acetamide scaffold also possessed Aβ 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 Aβ aggregation and neurotoxicity, and may provide a further platform for the development of novel Alzheimer's disease-modifying pharmacotherapies.
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, Faculty of Health Sciences, The University of Adelaide, South Australia, Australia.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Das
authors.affiliation: Discipline of Pharmacology, Adelaide Medical School, Faculty of Health Sciences, The University of Adelaide, South Australia, Australia. Electronic address: scott.smid@adelaide.edu.au.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Smid
mesh_terms: D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D048289:Imidazolidines / Q000494:pharmacology*; D046529:Microscopy, Electron, Transmission; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D009474:Neurons / Q000166:cytology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D016716:PC12 Cells; D051381:Rats; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D048289:Imidazolidines; D018696:Neuroprotective Agents; D014230:Triazoles
keywords: Alzheimer's disease; Amyloid β; Benzoxazole; Imidazolidine; Triazole; Virtual screening