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 complex multifactorial nature of AD, a fact that has prompted the design of new Multi-Target-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.

Keywords: Alzheimer's disease; anti-β-amyloid aggregation; donepezil; multi-target-directed ligands; oxidative stress.

Figure 1

Structure of AChE displaying the active site at the bottom of a narrow gorge, lined with hydrophobic amino-acid side chains within the catalytic triad, the choline binding site, and the peripheral binding site (Reproduced, with permission from Soreq and Seidman, 2001).

Figure 2

Role of APP cleavage processing in AD and microglial activation (Reproduced, with permission from Heppner et al., 2015).

Figure 3

Prevailing connections between oxidative stress and other key players in AD (Reproduced, with permission from Mattson, 2004).

Figure 4

Chemical structures of FDA-approved agents for use in AD: tacrine (1), donepezil (2), rivastigmine (3), galantamine (4), and memantine (5).

Figure 5

Scheme of the therapeutic design strategy of MTDL for the treatment of the multifaceted nature of AD pathology.

Figure 6

Structure of compounds PF9601N, ASS234, and the MTDL1-4 described in this review.

Figure 7

Design strategy of ASS234. IC₅₀ values (in μM) of donepezil, PF9601N and ASS234 inhibiting both ChEs and MAO activities are shown Bolea et al. (2011).

Figure 8

Schematic representation of ASS234 targets involved in AD pathogenesis. ASS234 forms a N5 flavin adduct (like clorgyline) with MAO A and it is able to block AChE-induced Aβ aggregation. ASS234 shows antioxidant and anti-apoptotic properties and it is able to induce neuroprotection through the Wnt pathway. ASS234 also shows less toxicity than donepezil in HepG2 cells (With permission of Bolea et al., 2013b).

Figure 9

Designed structure of hybrid MTDL1 and IC₅₀ values for the inhibition of ChE and MAO enzymes (Bautista-Aguilera et al., 2014a).

Figure 10

Structure of hybrid MTDL2 and IC₅₀ values for the inhibition of ChEs and MAO enzymes (Bautista-Aguilera et al., 2014b).

Figure 11

Structure of hybrid MTDL3 and IC₅₀ values for the inhibition of ChEs and MAO enzymes (Wang et al., 2014).

Figure 12

Structure of hybrid MTDL-4 and IC₅₀ values for the inhibition of ChEs and MAO enzymes (Wu et al., 2015).