Selected 1, 3‐Benzodioxine‐Containing Chalcones as Multipotent Oxidase and Acetylcholinesterase Inhibitors. (14th October 2020)

• Record Type: Journal Article
• Authors: Jeong, Geum Seok; Kaipakasseri, Swafvan; Lee, Sang Ryong; Marraiki, Najat; Batiha, Gaber El‐Saber; Dev, Sanal; Palakkathondi, Ashique; Kavully, Fathima Sahla; Gambacorta, Nicola; Nicolotti, Orazio; Mathew, Bijo; Kim, Hoon
• Is Part Of: ChemMedChem. Volume 15:Number 23(2020)
• Page Start: 2257
• Page End: 2263
• Publication Date: 2020-10-14
• Subjects: chalcones -- dual-target -- monoamine -- oxidase -- acetylcholinesterase -- kinetics -- docking analysis; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000491
• Languages: English
• ISSNs: 1860-7179

Abstract

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 IC50 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 (IC50 value of 0.023 μM). On the other hand, CD10 and CD8 inhibited AChE with IC50 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 Ki 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. Abstract : Hitting neurodegenerative disorders : A 1, 3‐benzodioxine chalcone derivative CD8 potently and non‐selectively inhibited MAO‐A and MAO‐B (IC50 = 0.023 and 0.026 μM, respectively). CD10 and CD8 effectively, competitively, and reversibly inhibited AChE with IC50 values of 5.40 and 9.57 μM, respectively. CD8 and CD10 showed high adsorptions and blood‐brain barrier permeabilities via in silico analysis, and they can be considered potential dual‐targeting inhibitors of MAO and AChE.