Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: Application to a pyrimidine-2,4-diamine template

We investigated a group of 2-benzylpiperidin-N-benzylpyrimidin-4-amines with various electron-withdrawing or electron-donating groups (EWGs or EDGs, respectively) as multi-targeted Alzheimer's disease (AD) therapeutics. The synthesized derivatives were screened for anti-cholinesterase (AChE and BuChE), anti-A beta-aggregation (AChE- and self-induced) and anti-beta-secretase (BACE-1) activities in an effort to identify lead, multifunctional candidates as part of our multi-targeted approach to treat AD. Biological assessment revealed that the nature of the substituent on the C-4 benzylamine group (e.g., halogen vs methoxy-based) greatly affected the biological profile. In vitro screening identified N-2-(1-benzylpiperidin-4-yl)-N-4-(3,4-dimethoxybenzyl) pyrimidine-2,4-diamine (7h) as the lead candidate with a dual ChE (AChE IC50 = 9.9 mu M; BuChE IC50 = 11.4 mu M), A beta-aggregation (AChE-induced = 59.3%; self-induced = 17.4% at 100 mu M) and BACE-1 (34% inhibition at 10 mu M) inhibitory profile along with good cell viability (% neuroblastoma cell viability at 40 mu M = 81.0%). Molecular modeling studies indicate that a central pyrimidine-2,4-diamine ring serves as a suitable template to develop novel small molecule candidates to target multiple pathological routes in AD. (C) 2012 Elsevier Ltd. All rights reserved.