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Selected 1,3‐Benzodioxine‐Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors
Author(s) -
Jeong Geum Seok,
Kaipakasseri Swafvan,
Lee Sang Ryong,
Marraiki Najat,
Batiha Gaber ElSaber,
Dev Sanal,
Palakkathondi Ashique,
Kavully Fathima Sahla,
Gambacorta Nicola,
Nicolotti Orazio,
Mathew Bijo,
Kim Hoon
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000491
Subject(s) - acetylcholinesterase , chemistry , butyrylcholinesterase , monoamine oxidase , monoamine oxidase b , cholinesterase , stereochemistry , aché , in vitro , pharmacology , monoamine oxidase a , enzyme , ic50 , docking (animal) , biochemistry , biology , medicine , nursing
Abstract Chalcones are considered effective templates for the development of monoamine oxidase (MAO) and cholinesterase (ChE) inhibitors. The present work describes the syntheses of selected 1,3‐benzodioxine‐containing chalcones ( CD3, CD8 and CD10 ), and their inhibitory activities against MAO‐A, MAO‐B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compound CD8 most potently inhibited MAO‐B with an IC 50 value of 0.026 μM, followed by CD10 and CD3 (1.54 and 1.68 μM, respectively). CD8 potently and non‐selectively inhibited MAO‐A (IC 50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC 50 values of 5.40 and 9.57 μM, respectively. Kinetics and reversibility experiments showed that all synthesized molecules were competitive and reversible inhibitors, and the K i values of CD8 for MAO‐A and MAO‐B were 0.018 and 0.0019 μM, respectively. By in vitro and in silico analyses, all compounds were found to have high passive human gastrointestinal absorptions, blood‐brain barrier permeabilities, and non‐toxicities. Molecular docking simulations revealed that docking affinity of each compound for MAO‐B was higher than that for MAO‐A. The results indicate that CD8 is a potent non‐selective MAO inhibitor, and CD10 is an effective selective MAO‐B inhibitor, and both possess AChE inhibitory activity. Therefore, we suggest that CD8 and CD10 be considered potential dual‐targeting inhibitors of MAO and AChE for the treatment of various neurodegenerative disorders.