From Hybrids to New Scaffolds: The Latest Medicinal Chemistry Goals in Multi-target Directed Ligands for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder affecting cognition, behavior, and function, being one of the most common causes of mental deterioration in elderly people. Once thought as being just developed because of β amyloid depositions or neurofibrillary Tau tangles, during the last decades, numerous AD-related targets have been established, the multifactorial nature of AD became evident. In this context, the one drug-one target paradigm has resulted in being inefficient in facing AD and other disorders with complex etiology, opening the field for the emergence of the multitarget approach. In this review, we highlight the recent advances within this area, emphasizing in hybridization tools of well-known chemical scaffolds endowed with pharmacological properties concerning AD, such as curcumin-, resveratrol-, chromone- and indole-. We focus mainly on well established and incipient AD therapeutic targets, AChE, BuChE, MAOs, β-amyloid deposition, 5-HT4 and Serotonin transporter, with the aim to shed light about new insights in the AD multitarget therapy.

Keywords: 5-HT receptors; Alzheimer disease; cholinesterase inhibitors; monoamine oxidase.; multi-target directed ligands; serotonin transporter; tau protein; β – amyloid aggregation.

Fig. (1)

Approved drugs for AD treatment.

Fig. (2)

Chemical structures of (A) curcumin, (B) demethoxycurcumin and (C) bisdemethoxycurcumin.

Fig. (3)

Multi-target directed ligands based on donepezil and curcumin scaffolds reported by Yan et al.

Fig. (4)

Water-soluble functionalized curcumin derivatives reported by Wang et al.

Fig. (5)

Functionalized curcumin derivatives described by Cui and coworkers.

Fig. (6)

Curcumin derivatives reported by Lakey-Beitia et al.

Fig. (7)

Curcumin asymmetric derivatives as amyloid β and tau aggregation inhibitors.

Fig. (8)

Multi-target direct ligands based on rivastigmine and curcumin hybrids investigated by Li et al.

Fig. (9)

Fusion of tacrine and curcumin as actives hybrids.

Fig. (10)

Feruloyl-donepezil hybrids as MTDLs synthesized by Dias et al.

Fig. (11)

Isomers of resveratrol.

Fig. (12)

Resveratrol derivatives as MTDLs against AD.

Fig. (13)

Fusion of resveratrol and clioquinol as MTDLs.

Fig. (14)

Resveratrol-Tacrine hybrids reported by Jeřábek et al.

Fig. (15)

Novel maltol-resveratrol hybrids as MTDLs reported by Cheng et al.

Fig. (16)

Prenylated and geranylated resveratrol derivatives.

Fig. (17)

Isoprenylation-Resveratrol dimer derivatives described by Tang et al.

Fig. (18)

Deferiprone-resveratrol hybrids.

Fig. (19)

Pyridoxine-Resveratrol hybrids Mannich base derivatives.

Fig. (20)

Chromone.

Fig. (21)

Chromone and benzylpiperidine moieties of donepezil as multifunctional agents.

Fig. (22)

Donepezil + chromone + melatonin hybrids as multitarget agents for AD.

Fig. (23)

Chromone derivatives reported by Li et al.

Fig. (24)

Chromone 2- and 3-phenylcarboximide derivatives.

Fig. (25)

MTDLs based on chromen-4-one reported by Singh et al.

Fig. (26)

Coumarin versus chromone scaffold reported by Fonseca et al.

Fig. (27)

α-Aminophosphonate -functionalized chromone as MTDLs.

Fig. (28)

Indole structure.

Fig. (29)

Melatonin-benzyl pyridinium bromides derivates synthesized by Luo et al.

Fig. (30)

MTDLs based on donepezil and indole scaffolds reported by Bautista-Aguilera et al.

Fig. (31)

Donepezil-melatonin derivatives reported by Wang et al.

Fig. (32)

Tadalafil derivates as AChE/PDE5 dual inhibitors.

Fig. (33)

Donecopride, RS67333 and donepezil hybrid designed by Lecoutey et al.

Fig. (34)

Donecopride derivates as MTDL reported by Lalut et al.

Fig. (35)

Indolylpropyl benzamidopiperazines derivates with AChE and SERT activities reported by Rodríguez-Lavado et al.