Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino‐Alkyl‐Substituted Fluoro‐Chalcones Derivatives

Abstract

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3a˜3l) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino-alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase (IC50 = 0.21 ± 0.03 μmol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE) = 65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme.

Arylidene indanone scaffold: medicinal chemistry and structure–activity relationship view

“…3) having 2-pyrrolidinyl ethoxy at the 4 0 -position and a uoro group at the 4-position showed potency for AChE compared to BuChE and this was correlated by docking analysis which showed a dual interaction with the catalytic site and the PAS of the AChE enzyme. 47 The bis(4-uorophenyl)methyl piperazine group (see R of 11c in Fig. 3) was introduced on the 4-position of the arylidene group (14a; Fig.…”

Tertiary amine derivatives of chlorochalcone as acetylcholinesterase (AChE) and buthylcholinesterase (BuChE) inhibitors: the influence of chlorine, alkyl amine side chain and α,β-unsaturated ketone group

“…Among them, compound 4l had the highest selectivity as 667 fold. Compared with the tertiary amine derivatives of fluorochalcone in our previous report, compound 4l showed higher selectivity against AChE than that of fluorochalcone derivatives 27 .…”

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

“…The resulting hybrid 102 ( Figure 22) possessed very good AChE inhibition (IC 50 = 7300 nM) along with anti-oxidant activity (EC 50 = 303 µM) [165]. Among the various reported chalcone derivative [166,167] the 103 ( Figure 22) was a mixed-type inhibition against AChE (IC 50 = 210 nM) which was 50-fold more potent than the drug rivastigmine (IC 50 = 10540 nM) [168]. The 1-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles 104 ( Figure 22, Table 6) was found to be a competitive AChE inhibitor (IC 50 = 64000 nM) in electric eel [169].…”