Synthesis, biological evaluation and molecular docking study of novel piperidine and piperazine derivatives as multi-targeted agents to treat Alzheimer's disease. Issue 5 (1st March 2015) - Meena, Poonam
Graphical abstract: Abstract: Development of Multi-Target Directed Ligands (MTDLs) has emerged as a promising approach for targeting complex etiology of Alzheimer's disease (AD). Following this approach, a new series of N′-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine derivatives were designed, synthesized and biologically evaluated as inhibitors of cholinesterases (ChEs), amyloid-beta (Aβ) self aggregation and also for their radical scavenging activity. The in vitro studies showed that the majority of synthesized derivatives strongly inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 values in the low-nanomolar range, and were clearly more potent than the reference compound donepezil in this regard. Among them, inhibitors5h and5k, strongly inhibited AChE, with IC50 value of 6.83 nM and 2.13 nM, respectively, and particularly, compound5k was found to be highly selective for AChE (∼38-fold). Moreover, both kinetic analysis of AChE inhibition and the docking study suggested that5k binds simultaneously to catalytic active site and peripheral anionic site of AChE. Besides, these compounds also exhibited greater ability to inhibit self-induced Aβ1–42 aggregation at 25 μM with percentage inhibition from ∼54% to 89% and specially compound5k provided highest inhibition (88.81%). Also, the derivatives containing methoxy and hydroxy groups showed potent oxygen radical absorbance capacity (ORAC) ranging from 2.2- to 4.4-fold of the Trolox value. Furthermore, results of ADMET studies suggested that all compounds exhibited appropriate drug like properties. Taken together, these results suggest that5k might be a promising lead compound for further AD drug development.