Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

Abstract

HIGHLIGHTS• ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.• Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.• MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal-chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.• The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).• MTDL-4 showed higher affinity toward AChE, BuChE.• MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.• MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy.Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept ® ) but with limited therapeutic success. This might be due to the Unzeta et al.New MTDLs for Alzheimer's Disease complex multifactorial nature of AD, a fact that has prompted the design of new MultiTarget-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Interestingly, some drug candidates have emerged from MTDL design showing promising multi-target properties and have been submitted to extensive bio-pharmacological profiling (Cavalli et al, 2008). Members of the Cost ACTION CM1103 (http://www.cost.eu/COST_Actions/cmst/CM1103) have designed, synthetized and evaluated new different MTDL compounds acting on ChE and MAO-I that may elicit better outcomes in the complex nature of AD than the current selective drugs (Benek et al, 2015; Ismaili et al, 2016; Unzeta et al, 2016). Moreover, MAO-Is with additional ion-chelating and/or antioxidant activities, compounds with dual MAO-I and adenosine A2aR antagonist activity have been characterized (Pisani et al, 2011; Guzior et al, 2015).…”

Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

“…Donepezil is well known as a cholinesterase inhibitor that is approved for AD treatment. Donepezil is effective in improving cognitive function [3738]. Furthermore, the Aβ 1-42 -infused rat model that we used here shows the pathological hallmarks of AD, including amyloid deposition, robust neuroinflammation, synaptic marker changes, neuronal death, and memory impairments [2333].…”

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Several libraries of donepezil‐linked hybrids had been reported in which the N ‐benzylpiperidine motif of donepezil was linked to the N ‐propargylamine motif of PF9601N ( 237 ), a potent and selective MAO‐BI with neuroprotective effects via means of different heterocyclic ring systems like indole, pyridine, or 8‐hydroxyquinoline; with special emphasis on compound ASS234 ( 238 ), an N ‐propargylindole derivative (Figure ) . ASS234 { N ‐[5‐(3‐(1‐benzylpiperidin‐4‐yl)propoxy)‐1‐methyl‐1 H ‐indol‐2‐ylmethyl]‐ N ‐methylprop‐2‐yn‐1‐amine} ( 238 ) was developed with a view to combine the anticholinergic property of donepezil with a propargylamine moiety derived from selective MAO‐BI, PF9601N ( 237 ) .…”

“…Donepezil‐linked hybrids ( 237‐242 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”