Acetylcholinesterase Inhibitors:  Synthesis and Structure−Activity Relationships of ω-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl Derivatives

Abstract

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.

How accurate can molecular dynamics/linear response and Poisson-Boltzmann/solvent accessible surface calculations be for predicting relative binding affinities? Acetylcholinesterase huprine inhibitors as a test case

“…The positive value of the coecient (b) in Eqs. (8) and (9) implies that the binding anity increases as the electrostatic dierence between bound and unbound states of the inhibitor does. The root-mean-square deviation (rmsd) between experimental and predicted (from Eq.…”

“…Tacrine (Cognex) was the ®rst inhibitor approved for the palliative treatment of Alzheimer's disease senile dementia, though its clinical ecacy is limited owing to undesirable side eects, especially hepatotoxicity [3]. Research eorts have concentrated on analogues of tacrine [4], huperzine [5] and derivatives of physostigmine [6], N-benzylpiperidines [7], and xanthones [8], leading to the discovery of the recently marketed donepezil (Aricept) [9] and rivagstimine (Exelon) [10]. The synthesis, in vitro pharmacology and molecular modeling of a series of tacrine±huperzine A hybrids (huprines; Fig.…”

3D-pharmacophore model based virtual screening to identify dual-binding site and selective acetylcholinesterase inhibitors

“…A total of 80 xanthostigmine-based AChE inhibitors were collected from different literatures (Belluti et al, 2005;Piazzi et al, 2007;Rampa et al, 2001;Rampa et al, 1998). The method for determining the AChE inhibitory activity is same and obtained from the same lab for these 80 compounds.…”

Novel acetylcholinesterase inhibitors: Synthesis and structure–activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

“…Compound D (m = 7) displayed AChE inhibition ability nearly equal to compound C. The tricyclic ring of compound C was not able to reach Trp279, but showed stacking interaction with Tyr330, Phe331 and Tyr121, which existed on the halfway of the gorge. The tricyclic ring of compound D reached Trp279 and bound Trp279 well [3,4]. Compound E and F, designed and synthesized as dual inhibitors of AChE and SERT, had a high affinity for AChE in the nanomolar range (compound E with IC 50 = 14 nM, 785-fold higher than rivastigmine, and compound F with IC 50 = 36 nM, 305-fold higher than rivastigmine) [5].…”