Multifunctional Ligand Approach: Search for Effective Therapy Against Alzheimer’s Disease

Abstract

Alzheimer' s disease is a progressive, incurable, and complex neurodegenerative disease. Currently, an effective treatment that can slow down or stop the damage and death of neurons, which is a characteristic of Alzheimer' s disease, is lacking. Taking into account the complex nature of the disease, a multitarget design approach has been developed for the production of new potential anti-AD agents. The goal of this approach is to create a single molecule that can interact selectively with several desired molecular targets relevant to the disease. This strategy was successfully developed two decades ago and has been improved in recent years. This chapter describes the progress made in the discovery and design of selected multitargeted drugs based on molecular targets, which can be used for treating Alzheimer' s disease. The most promising among these drugs are the molecules having properties that are valuable not only in the symptomatic therapy but also in the causal treatment of the disease. The main hypotheses of Alzheimer' s disease, such as β-amyloid (Aβ), tau, and cholinergic, suggest that compounds capable of inhibiting the aggregation of neurotoxic Aβ-amyloid peptide and tau protein, and improving the cholinergic neurotransmission, may possess such properties.

Non-Pharmacologic Alternatives in the Management of Alzheimer’s Disease

“…Immunotherapy has been explored as a possible option as the targeted-directed therapy may also have diseasemodifying potential; however, this has been unsuccessful [4]. Other attempts include epigenetic modifications [5], multifunctional ligand approach [6], and targeting metal homeostasis [7], to name a few. Drug discovery and several translational research also consider these new approaches.…”

Bis-Amiridines as Acetylcholinesterase and Butyrylcholinesterase Inhibitors: N-Functionalization Determines the Multitarget Anti-Alzheimer’s Activity Profile

“…There is considerable interest in the discovery and development of multi-target-directed ligands (MTDLs), also known as multifunctional molecules or multitarget drugs or agents [ 4 , 40 , 49 , 50 ]. This interest has arisen from the realization that complex diseases such as AD involve dysfunctions in multiple processes and targets, so that the former approach of searching for a single druggable target for a given disease is unlikely to be successful in this case [ 51 , 52 , 53 , 54 , 55 ].…”

Synthesis and biological evaluation of benzimidazoles/1,3,5-triazine-2,4-diamine hybrid compounds: a new class of multifunctional alzheimer targeting agents

“…36,37 In many previous studies, the Donepezil N-benzylpiperidine nucleus has been used to design new compounds. [38][39][40] In the case of compounds bearing 1H-benzo[d]imidazole rings, innovative derivatives of tetrahydroisoquinoline-benzimidazole hybrids, in particular the derivative II (Scheme 1), have demonstrated significant anti-neuroinflammatory activity (IC 50 = 5.07 mM against nitric oxide production), moderate human b-secretase inhibitory activity (BACE-1) (65.7% inhibition at 20 mM), and potent neuroprotective activity. 41 Other studies have proven that the compounds with an aminopyridine moiety (Scheme 1, III) can be good blockers for BACE1 (BACE-1 affinity more than 1 nM).…”

“…36,37 In many previous studies, the Donepezil N -benzylpiperidine nucleus has been used to design new compounds. 38–40…”