Guzior_2015_Eur.J.Med.Chem_92C_738

The presented study describes the synthesis, pharmacological evaluation (AChE and BCHE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 muM). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 muM) possesses additional properties, such as the ability to inhibit Abeta aggregation (65.96% at 10 muM) and a neuroprotective effect against Abeta toxicity at 1 and 3 muM. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders.