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Design, Synthesis, and Cholinesterase Inhibition Assay of Coumarin-3-Carboxamide-N-Morpholine Hybrids As New Anti-Alzheimer Agents Publisher Pubmed



Tehrani MB1 ; Rezaei Z1 ; Asadi M1 ; Behnammanesh H1 ; Nadri H2 ; Afsharirad F1 ; Moradi A2 ; Larijani B3 ; Mohammadikhanaposhtani M4 ; Mahdavi M3
Authors
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Authors Affiliations
  1. 1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 1417653761, Iran
  2. 2. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, 8915173160, Iran
  3. 3. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, 1417653761, Iran
  4. 4. Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, 4717647745, Iran

Source: Chemistry and Biodiversity Published:2019


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. © 2019 Wiley-VHCA AG, Zurich, Switzerland
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