Panek_2016_Eur.J.Med.Chem_125_676

The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, beta-secretase and beta-amyloid inhibitory activities. In vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50 values ranging from 0.83 muM to 19.18 muM. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 muM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 muM) and inhibitory activity against hBACE1 (33.61% at 50 muM). Compound 52 is a selective AChE inhibitor (IC50 AChE = 6.47 muM) with BACE1 inhibitory activity (26.3% at 50 muM) and it displays the most significant Abeta anti-aggregating properties among all the obtained compounds (39% at 10 muM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.