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Potent and highly selective dual‐targeting monoamine oxidase‐B inhibitors: Fluorinated chalcones of morpholine versus imidazole
Author(s) -
Mathew Bijo,
Baek Seung C.,
Thomas Parambi Della G.,
Lee Jae P.,
Mathew Githa E.,
Jayanthi Sivaraman,
Vinod Devaraji,
Rapheal Clariya,
Devikrishna Vinod,
Kondarath Shahin Shad,
Uddin Md. Sahab,
Kim Hoon
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201800309
Subject(s) - morpholine , chemistry , monoamine oxidase , acetylcholinesterase , stereochemistry , imidazole , piperidine , selectivity , monoamine oxidase b , docking (animal) , enzyme inhibitor , enzyme , biochemistry , organic chemistry , medicine , nursing , catalysis
Two series of fluorinated chalcones containing morpholine and imidazole‐based compounds ( f1–f8 ) were synthesized and evaluated for recombinant human monoamine oxidase (MAO)‐A and ‐B as well as acetylcholinesterase inhibitory activities. Our results indicate that morpholine containing chalcones are highly selective MAO‐B inhibitors having reversibility properties. All the imidazole‐based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds, (2 E )‐3‐(3‐fluorophenyl)‐1‐[4‐(morpholin‐4‐yl)phenyl]prop‐2‐en‐1‐one ( f2 ) showed potent inhibitory activity for recombinant human MAO‐B (IC 50 = 0.087 μM) with a high selectivity index (SI) of 517.2. In the recovery experiments using dialysis, the residual activity of MAO‐B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the K i values of f1 and f2 for MAO‐B were 0.027 and 0.020 μM, respectively, with competitive patterns. All the morpholine‐based compounds ( f1 – f4 ) showed moderate inhibition toward acetylcholinesterase with IC 50 values ranging between 24 and 54 μM. All morpholine‐containing compounds exhibit good blood–brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO‐B inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies.