Profiling donepezil template into multipotent hybrids with antioxidant properties

Abstract

Alzheimer's disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer's disease.

Keywords: Acetylcholinesterase; Alzheimer’s disease; donepezil; multi-target directed ligands; oxidative stress.

Graphical abstract

Figure 1.

Currently used AChEIs donepezil, galantamine and rivastigmine. Tacrine is no longer approved for AD treatment. Memantine act as NMDA receptor antagonist. Structures of human AChE (PDB ID: 4EY7) and GluN1A-GluN2B NMDA receptor (PDB ID: 4PE5) were downloaded from Protein Data Banka (http://www.rcsb.org) and created with PyMol viewer 1.3.

Figure 2.

Donepezil-related coumarin derivatives.

Figure 3.

Ferulic acid hybrids possessing antioxidant and anticholinesteratic properties.

Figure 4.

Curcumin-based hybrids with antioxidant properties.

Figure 5.

“Selenpezil” derivatives 21 and 22 based on fused ebselen with donepezil.

Figure 6.

Indane-based ChEIs 23–32.

Figure 7.

Bio-oxidizable pro-drugs 34 forming charged entities after oxidative activation 33. The proof-of-concept was firstly validated on rivastigmine-like analogue – the upper part of the Figure.

Figure 8.

The MTDLs combining melatonin and donepezil templates.

Figure 9.

Melatonin-N-benzylpyridinium bromide hybrid 38.

Figure 10.

The most potent analogues 39–42 related to donepezil-8HQ hybrids.

Figure 11.

Donepezil-based derivatives with glutamic acid.

Figure 12.

Structures of lipoic acid and the most active lipoic-N-benzylpiperidine hybrids (R)-46 and (S)-46.

Figure 13.

The most active AChEIs 48 and 49 from N-benzylpiperidine-diarylthiazole, 5,6-dimethoxy-indanone benzenamides, and N′-(4-benzylpiperidin-/piperazin-/benzhydrylpiperazin-1-yl)alkylamine families, respectively.