Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

Abstract

The review summarizes research into the highly relevant topics of cholinesterase and amyloid aggregation inhibitors connected to tacrine congeners, both of which are associated with neurogenerative diseases. Various opinions will be discussed regarding the dual binding site inhibitors which are characterized by increased inhibitor potency against acetylcholin/butyrylcholine esterase and amyloid formation. It is suggested that these compounds can both raise levels of acetylcholine by binding to the active site, and also prevent amyloid aggregation. In connection with this problem, the mono/dual binding of the multifunctional derivatives of tacrine, their mode of action and their neuroprotective activities are reported. The influence of low molecular compounds on protein amyloid aggregation, which might be considered as a potential therapeutic strategy in the treatment of Alzheimer's disease is also reported. Finally, attention is paid to some physico-chemical factors, such as desolvation energies describing the transfer of the substrate solvated by water, the metal-chelating properties of biometals reacting with amyloid precursor protein, amyloid beta peptide and tau protein.

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

“…The active site is composed of two subsites. In the catalytic anionic subsite (CAS), it has been proposed that the choline moiety in AChE is stabilized principally via a cation-p interaction with Trp84, and also interacts with Glu199 and Phe330 [5,13]. A similar cation-p interaction occurs in human BuChE, where Trp82 interacts with the product choline and the substrate butyrylthiocholine [14].…”

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

“…In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.…”

“…[9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity. 13,14 The acetylcholine binding site of AChE is located at the base of a deep hydrophobic channel measuring approximately 20 Å in length.…”

“…45 Despite the plethora of synthetic and natural ChEIs, different extents of chiral selectivity have been observed for reversible, irreversible or pseudo-irreversible inhibitors. 10,[46][47][48] For instance, several studies of structural elements of ChEs are being gradually unraveled by X-ray crystallography, kinetic experiments and computational techniques. 10 However, the lack of chiral prototypes as ChEIs in both enantiomeric forms is limited and demand further studies.…”

“…In addition, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (Namenda ® ) is also used. [9][10][11] However, none of these therapeutic options represent a real cure.The cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are enzymes which are found in the central nervous system (CNS) and catalyze the hydrolysis of ACh efficiently but at different rates. [9][10][11][12] However, as AD progresses, the activity of AChE decreases, while that of BuChE significantly increases and may even surpass the AChE activity.…”