Structure-based design of novel donepezil-like hybrids for a multi-target approach to the therapy of Alzheimer's disease

Alzheimer's disease (AD) is a widespread multifactorial aging-related pathology, which includescholinergic deficit among its main causes. Following a multi-target design strategy, the structure of theapproved drug donepezil was taken as the starting point for generating some new potential multifunctional compounds. Therefore, a series of twenty molecular hybrids were synthesized and assayedagainst three different enzymes, namely the well-established targets acetylcholinesterase (AChE) andbutyrylcholinesterase (BChE), and the innovative one fatty acid amide hydrolase (FAAH). In silico studiesconfirmed the interaction of benzylpiperidine and the benzylpiperazine isostere with the catalyticanionic site (CAS) of AChE, while the aryloxycarbonyl portion appeared to be important for the interaction with the peripheral site (PAS). A QSAR study was carried out on AChE inhibition data, whichrevealed that the inhibition potency seems to depend upon the length of the spacer and the number ofpolar atoms. The docking poses of selected compounds within BChE and FAAH were also calculated.Furthermore, pharmacokinetics and drug-likeness properties were assessed by chemoinformatic tools.Several piperidine derivatives (in particular compound 10) showed interesting profiles as multi-targetdirected agents, while the lead piperazine derivative 12 (SON38) was found to be a more potent andselective AChE inhibitor (IC50 ¼ 0.8 nM) than donepezil, besides being able to bind bivalent coppercations (pCu ¼ 7.9 at physiological pH). Finally, the selected lead compounds (10 and 12, SON38) did notshow significant cytotoxicity on SH-SY5Y and HepG2 cells at the highest tested concentration (100 mM) ina MTT assay