5,6-Dimethoxybenzofuran-3-one derivatives: a novel series of dual Acetylcholinesterase/Butyrylcholinesterase inhibitors bearing benzyl pyridinium moiety

Abstract

BackgroundSeveral studies have been focused on design and synthesis of multi-target anti Alzheimer compounds. Utilizing of the dual Acetylcholinesterase/Butyrylcholinesterase inhibitors has gained more interest to treat the Alzheimer’s disease. As a part of a research program to find a novel drug for treating Alzheimer disease, we have previously reported 6-alkoxybenzofuranone derivatives as potent acetylcholinesterase inhibitors. In continuation of our work, we would like to report the synthesis of 5,6-dimethoxy benzofuranone derivatives bearing a benzyl pyridinium moiety as dual Acetylcholinesterase/Butyrylcholinesterase inhibitors.MethodsThe synthesis of target compounds was carried out using a conventional method. Bayer-Villiger oxidation of 3,4-dimethoxybenzaldehyde furnished 3,4-dimethoxyphenol. The reaction of 3,4-dimethoxyphenol with chloroacetonitrile followed by treatment with HCl solution and then ring closure yielded the 5,6-dimethoxy benzofuranone. Condensation of the later compound with pyridine-4-carboxaldehyde and subsequent reaction with different benzyl halides afforded target compounds. The biological activity was measured using standard Ellman’s method. Docking studies were performed to get better insight into interaction of compounds with receptor.ResultsThe in vitro anti acetylcholinesterase/butyrylcholinesterase activity of compounds revealed that, all of the target compounds have good inhibitory activity against both Acetylcholinesterase/Butyrylcholinesterase enzymes in which compound 5b (IC50 = 52 ± 6.38nM) was the most active compound against acetylcholinesterase. The same binding mode and interactions were observed for the reference drug donepezil and compound 5b in docking study.ConclusionsIn this study, we presented a new series of benzofuranone-based derivatives having pyridinium moiety as potent dual acting Acetylcholinesterase/Butyrylcholinesterase inhibitors.

Synthesis and cytotoxic properties of novel (E)-3-benzylidene-7-methoxychroman-4-one derivatives

“…Structurally, SJ-172550 is characterized by having α,β-unsaturated carbonyl system attached to the 2-(2-chloro-6-ethoxyphenoxy)acetic acid methyl ester. Accordingly, in continuation of our research program to find novel anti-cancer agents [12-16] and considering the diverse biological activities of rigid chalcones [17], we have synthesized a series of 3-benzylidene-4-chromanones bearing 2-(2-chloro-6-alkoxyphenoxy) acetic acid esters. The related analogs of 3-benzylidene-4-chromanones were also prepared for more studying of structure-activity relationships (Figure 1).…”

Synthesis, molecular modeling studies, ADME prediction of arachidonic acid carbamate derivatives, and evaluation of their acetylcholinesterase activity

“…The presence of an electron‐donating methoxy group at the para position of the phenyl ring reduced the inhibition potential against the AChE enzyme. According to literature, substitution of electron‐withdrawing groups, such as halogens, on the phenyl ring make the compounds more active than the unsubstituted compound while substitution of electron‐donating groups, such as methyl groups, on the phenyl ring make the compounds less active (Nadri et al, ; Yoon et al, ). However, our observations have shown that the methoxy substituted compound 7g is more potent than its unsubstituted compound 7a (IC 50 = 29.9 ± 3.1 μM).…”

Synthesis and In vitro cytotoxic activity evaluation of (E)-16-(substituted benzylidene) derivatives of dehydroepiandrosterone

“…The benzylidene-substituted DHEA derivatives 1a-m were synthesized through the aldol condensation [36] of DHEA with corresponding benzaldehyde derivatives (Figure 2). …”