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.

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Urease is an important target for the treatment of Helicobacter pylori infection. In this study, several pharmacophores for the inhibition of urease were considered and coupled to design new molecules capable of acting as potent urease inhibitors. Literature review reveals that barbituric-hydrazine, phenoxy-1,2,3-triazole, and acetamide moieties are pharmacophores for urease inhibition. Therefore, in this study, the barbiturichydrazine-phenoxy-1,2,3-triazole-acetamide scaffold was designed and twelve derivatives 9 a-l of it were synthesized and evaluated. The urease inhibition assay of these compounds revealed that all new title compounds, except for one compound, with IC 50 values of 0.73 to 5.27 μM were more potent than standard inhibitor thiourea. The most potent compound inhibited urease in a mixed-type inhibition mode and interacted as well with the urease active site. In silico druglikeness and toxicity studies of the most potent compounds predicted that these compounds passed successfully Lipinski's rule of five and had no carcinogenicity on the rat.

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