Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

Rani Sasidharan; Bo Hyun Eom; Jeong Hyun Heo; Jong Eun Park; Mohamed A Abdelgawad; Arafa Musa; Nicola Gambacorta; Orazio Nicolotti; Sreedharannair Leelabaiamma Manju; Bijo Mathew; Hoon Kim

doi:10.1080/14756366.2020.1842390

Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations

J Enzyme Inhib Med Chem. 2021 Dec;36(1):188-197. doi: 10.1080/14756366.2020.1842390.

Authors

Rani Sasidharan^{1

2}, Bo Hyun Eom³, Jeong Hyun Heo³, Jong Eun Park³, Mohamed A Abdelgawad^{4

5}, Arafa Musa^{6

7}, Nicola Gambacorta⁸, Orazio Nicolotti⁸, Sreedharannair Leelabaiamma Manju², Bijo Mathew⁹, Hoon Kim³

Affiliations

¹ College of Pharmaceutical Science, Government T.D. Medical College, Alappuzha, India.
² Organic Chemistry Division, SAS, VIT University, Vellore, India.
³ Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea.
⁴ Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni Suef, Egypt.
⁶ Department of Pharmacogonosy, College of Pharmacy, Jouf University, Sakaka, Saudi Arabia.
⁷ Department of Pharmacogonosy, Al-Azhar University, Cairo, Egypt.
⁸ Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
⁹ Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, India.

Abstract

Nine compounds (MO1-MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC₅₀ value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC₅₀ = 6.1 µM), followed by MO9 (IC₅₀ = 12.01 µM) and MO7 most potently inhibited MAO-A (IC₅₀ = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (K_i = 0.018 µM); MO5 reversibly competitively inhibited AChE (K_i = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (K_i = 7.04 µM). MO1, MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

Keywords: Docking analysis; Morpholine-containing chalcone; acetylcholinesterase; dual-acting inhibitor; monoamine oxidase.

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Chalcones / chemical synthesis
Chalcones / chemistry
Chalcones / pharmacology*
Chlorocebus aethiops
Cholinesterase Inhibitors / chemical synthesis
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
HeLa Cells
Humans
Hydrogen Peroxide / antagonists & inhibitors
Hydrogen Peroxide / pharmacology
Molecular Docking Simulation
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry
Monoamine Oxidase Inhibitors / pharmacology*
Morpholines / chemistry
Morpholines / pharmacology*
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism
Structure-Activity Relationship
Vero Cells

Substances

Chalcones
Cholinesterase Inhibitors
Monoamine Oxidase Inhibitors
Morpholines
Reactive Oxygen Species
morpholine
Hydrogen Peroxide
Monoamine Oxidase
Acetylcholinesterase

Grants and funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Republic of Korea government (Grant No. NRF-2019R1A2C1088967 to H. Kim).