Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin‐3‐carboxamide‐N‐morpholine Hybrids as New Anti‐Alzheimer Agents

Abstract

A new series of coumarin‐3‐carboxamide‐N‐morpholine hybrids 5a–5l was designed and synthesized as cholinesterases inhibitors. The synthetic approach for title compounds was started from the reaction between 2‐hydroxybenzaldehyde derivatives and Meldrum's acid to afford corresponding coumarin‐3‐carboxylic acids. Then, amidation of the latter compounds with 2‐morpholinoethylamine or N‐(3‐aminopropyl)morpholine led to the formation of the compounds 5a–5l. The in vitro inhibition screen against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) revealed that most of the synthesized compounds had potent AChE inhibitory while their BuChE inhibitions are moderate to weak. Among them, propylmorpholine derivative 5g (N‐[3‐(morpholin‐4‐yl)propyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing an unsubstituted coumarin moiety and ethylmorpholine derivative 5d (6‐bromo‐N‐[2‐(morpholin‐4‐yl)ethyl]‐2‐oxo‐2H‐chromene‐3‐carboxamide) bearing a 6‐bromocoumarin moiety showed the most activity against AChE and BuChE, respectively. The inhibitory activity of compound 5g against AChE was 1.78 times more than that of rivastigmine and anti‐BuChE activity of compound 5d is approximately same as rivastigmine. Kinetic and docking studies confirmed the dual binding site ability of compound 5g to inhibit AChE.

Effects of Coumarinyl Schiff Bases against Phytopathogenic Fungi, the Soil-Beneficial Bacteria and Entomopathogenic Nematodes: Deeper Insight into the Mechanism of Action

“…Additionally, van der Waals interactions were noted between compound 9 and residues ILE-275, ASP-276 and ILE-287. The involvement of the mentioned residues from the AS, AP, and PAS was confirmed to contribute stability to the complex between AChE and synthetic inhibitors such as coumarin-triazole-amino acid hybrids [ 55 ], tyrosol 1,2,3-triazole analogs [ 56 ], coumarin-3-carboxamide-N-morpholine hybrids [ 57 ], chromone derivatives [ 28 ], and chromenyl coumarate [ 58 ].…”

Non‐aggregated and water soluble axially disubstituted silicon phthalocyanines: Synthesis and inhibitory effect on acetylcholinesterase enzyme

“…Alzheimer's disease (AD) is known as a neurodegenerative disorder of the central nervous system. Unfortunately, the incidence of this disorder is more in the elderly; even the disease can result in dementia and death in this current population 17 . Although AD contains some etiologies that can be characterized by an imbalance in the cholinergic nervous synapses, aggregation of β‐amyloid plaques, and occurring of neurofibrillary tangles, 18 its real etiology and pathogenesis have not been clarified yet 19 .…”

“…Unfortunately, the incidence of this disorder is more in the elderly; even the disease can result in dementia and death in this current population. 17 Although AD contains some etiologies that can be characterized by an imbalance in the cholinergic nervous synapses, aggregation of β-amyloid plaques, and occurring of neurofibrillary tangles, 18 its real etiology and pathogenesis have not been clarified yet. 19 But it is well-known in this disease that the levels of some neuromediators such as acetylcholine (ACh) and butyrylcholine (BCh) are imbalance in the brains of patients whose diagnosis with AD.…”

2H/4H-Chromenes—A Versatile Biologically Attractive Scaffold

“…One of the essential structural features of 4H-ch to impart miscellaneous activity is the occurrence of the fold along the oxygen axis. The molecules containing 2H/4H-ch scaffold exhibit noteworthy potency, such as anticancer (Afifi et al, 2017a ; Halawa et al, 2017 ; Elshaflu et al, 2018 ; Elnaggar et al, 2019 ; Luque-Agudo et al, 2019 ), anticonvulsant (Rawat and Verma, 2016 ), antimicrobial (Suvarna et al, 2017 ; Mashhadinezhad et al, 2019 ), anticholinesterase (Tehrani et al, 2019 ), antidiabetic activities (Soni et al, 2019 ), antituberculosis (Zhao et al, 2020 ), and inhibitory activity against monoamine oxidase (MAO) (Takao et al, 2019 ).…”