Advances Toward Multifunctional Cholinesterase and β-Amyloid Aggregation Inhibitors

Abstract

The emergence of a multitarget design approach in the development of new potential anti-Alzheimer's disease agents has resulted in the discovery of many multifunctional compounds focusing on various targets. Among them the largest group comprises inhibitors of both cholinesterases, with additional anti-β-amyloid aggregation activity. This review describes recent advances in this research area and presents the most interesting compounds reported over a 2-year span (2015-2016). The majority of hybrids possess heterodimeric structures obtained by linking structurally active fragments interacting with different targets. Multipotent cholinesterase inhibitors with β-amyloid antiaggregating activity may additionally possess antioxidative, neuroprotective or metal-chelating properties or less common features such as anti-β-secretase or τ-antiaggregation activity.

Conjugates of methylene blue with γ-carboline derivatives as new multifunctional agents for the treatment of neurodegenerative diseases

“…AChE plays an important role in the processing of Aβ through the interaction of its peripheral anionic site (PAS) with soluble amyloid-β peptides to promote their aggregation 8–10 . Based on these facts, drugs with such dual capabilities (i.e., inhibition of AChE catalytic activity and inhibition of AChE-induced Aβ aggregation) have been a subject of intensive research 11 . It is therefore reasonable to expect that these kinds of agents could simultaneously enhance cognition and engender neuroprotection 12,13 .…”

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

“…MTDLs which contain a pharmacophoric moiety derived from tacrine are potent BACE-1 inhibitors, inhibitors of tau-protein aggregation and possess additional properties (antioxidative, neuroprotective or metal chelating ability) [ 122 , 123 , 124 , 125 , 126 , 127 ] as well as another major chemical group consisting of donepezil-related compounds [ 121 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 ]. Moreover, miscellaneous compounds based on the cyanopyridine, quinazoline, quinoline, benzo-chromene, pyrimidinimine, and thiazole cores are inhibitors of both AChE and β-amyloid aggregation and some of them possess antioxidative properties and inhibitory potency against BACE-1 [ 137 ].…”

Dual targeting of cholinesterase and amyloid beta with pyridinium/isoquinolium derivatives

“…This includes: (a) GSK‐3β and tau aggregation inhibitors (Gandini et al, ), (b) AChE and monoamine oxidase B inhibitors, (Xu et al, ) (c) beta‐secretase 1 (BACE‐1) and glycogen synthase kinase 3 (GSK‐3β), (Prati et al, ) (d) the hybridization of AChE inhibitor and serotonergic subtype 4 receptor (5‐HT4R) activator (Rochais et al, ), (e) the introduction of antioxidant selenium into the Aβ‐aggregation inhibitor (Wang et al, ), and (f) the modifications of multifunctional anti‐AD curcumin scaffold (Di Martino et al, ). Despite these prior efforts, Aβ and cholinesterases remain to be of paramount significance (Mohamed & Rao, ; Panek, Wichur, Godyń, Pasieka, & Malawska, ; Tonelli et al, ). Presently, the only pharmacological therapy for AD apart from N‐methyl d ‐aspartate receptor antagonist memantine, are the cholinesterase inhibitors, that is, donepezil, rivastigmine, and galantamine (Figure ).…”

“…Despite these prior efforts, Aβ and cholinesterases remain to be of paramount significance (Mohamed & Rao, 2017;Panek, Wichur, Gody n, Pasieka, & Malawska, 2017;Tonelli et al, 2015). Presently, the only pharmacological therapy for AD apart from N-methyl Daspartate receptor antagonist memantine, are the cholinesterase inhibitors, that is, donepezil, rivastigmine, and galantamine ( Figure 2).…”