Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
Abstract
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 mu M to 19.18 mu M. The target compounds displayed inhibition of human beta-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50 mu M 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-l-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50 = 0.83 mu M) and inhibitory activity against hBACE1 (33.61% at 50 mu M).
Compound 52 is a selective AChE inhibitor (IC50 AchE = 6.47 mu M) with BACE1 inhibitory activity (26.3% at 50 mu M) and it displays the most significant A beta anti-aggregating properties among all the obtained compounds (39% at 10 mu M). 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.