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A New Potent and Selective Monoamine Oxidase‐B Inhibitor with Extended Conjugation in a Chalcone Framework: 1‐[4‐(Morpholin‐4‐yl)phenyl]‐5‐phenylpenta‐2,4‐dien‐1‐one
Author(s) -
Maliyakkal Naseer,
Eom Bo Hyun,
Heo Jeong Hyun,
Abdullah Almoyad Mohammad Ali,
Thomas Parambi Della Grace,
Gambacorta Nicola,
Nicolotti Orazio,
Beeran Asmy Appadath,
Kim Hoon,
Mathew Bijo
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.202000305
Subject(s) - chemistry , chalcone , monoamine oxidase , stereochemistry , monoamine oxidase b , monoamine oxidase a , cinnamaldehyde , selectivity , docking (animal) , benzylamine , enzyme kinetics , ic50 , active site , pharmacology , enzyme , biochemistry , in vitro , organic chemistry , medicine , nursing , catalysis
The general blueprint for the design of monoamine oxidase‐B (MAO‐B) inhibitors has been based on two phenyl or heteronuclei linked via a spacer of appropriate length. In this study, 1‐[4‐(morpholin‐4‐yl)phenyl]‐5‐phenylpenta‐2,4‐dien‐1‐one (MO10) was prepared by the condensation of 4′‐morpholinoacetophenone and cinnamaldehyde in basic alcoholic medium. MO10 was assessed for inhibitory activity against two human MAO isoforms, MAO‐A and MAO‐B. Interestingly, MO10 showed a remarkable inhibition against MAO‐B with an IC 50 value of 0.044 μM along with a selectivity index of 366.13. The IC 50 value was better than that of lazabemide (IC 50 value of 0.063 μM), which was used as a reference. Kinetics studies revealed that MO10 acted as a competitive inhibitor of MAO‐B, with a K i value of 0.0080 μM. The observation of recovery of MAO‐B inhibition, compared to reference levels showed MO10 to be a reversible inhibitor. MTT assays showed that MO10 was nontoxic to normal VERO cells with an IC 50 value of 195.44 μg/mL. SwissADME predicted that MO10 provided advantageous pharmacokinetics profiles for developing agents acting on the central nervous system, that is, high passive human gastrointestinal absorption and blood–brain barrier permeability. Molecular docking simulations showed that MO10 properly entered the aromatic cage formed by Y435, Y398, and FAD of the active site of MAO‐B. On the basis of these results, MO10 can be considered a promising starting compound in development of agents for the treatment of various neurodegenerative disorders.