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Ethoxylated Head of Chalcones as a New Class of Multi‐Targeted MAO Inhibitors
Author(s) -
Lakshminarayanan Balasubramanian,
Baek Seung Cheol,
Lee Jae Pil,
Kannappan Nagappan,
Mangiatordi Giuseppe Felice,
Nicolotti Orazio,
Subburaju Thillainayagam,
Kim Hoon,
Mathew Bijo
Publication year - 2019
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201901093
Subject(s) - acetylcholinesterase , selectivity , chemistry , monoamine oxidase b , aché , monoamine oxidase , stereochemistry , non competitive inhibition , enzyme , trifluoromethyl , biochemistry , organic chemistry , catalysis , alkyl
A series of eleven ethoxysubstituted chalcones ( E1 ‐ E11 ) were synthesized and investigated for their inhibitory potential towards human recombinant monoamine oxidase A and B (hMAO−A and hMAO−B, respectively) and acetylcholinesterase (AChE). IC 50 values of 4.63 ± 0.15 and 0.053 ± 0.003 μM were obtained for MAO−A and MAO−B, respectively, by the most interesting compound (2E)‐1‐(4‐ethoxyphenyl)‐3‐(4‐fluorophenyl)prop‐2‐en‐1‐one ( E7 ), and it was characterized by a high selectivity index (SI=87.4) for MAO−B. Inhibitions by E7 against MAO−A and MAO−B were recovered (75.9 and 74.5%, respectively) to near the levels of reversible references (77.1 and 77.4%, respectively). The inhibition modes of E7 for MAO−A and MAO−B were competitive with K i values of 2.65 ± 0.064 and 0.011 ± 0.0011 μM, respectively. Compounds (2 E )‐1‐(4‐ethoxyphenyl)‐3‐(4‐ethylphenyl) prop‐2‐en‐1‐one ( E10 ) and (2 E )‐1‐(4‐ethoxyphenyl)‐3‐[4‐(trifluoromethyl)phenyl]prop‐2‐en‐1‐one ( E11 ) showed good inhibitions against AChE with IC 50 values of 2.86 ± 0.041 and 3.23 ± 0.0073 μM, respectively. A combined molecular docking/MM‐GBSA approach was used that employed quantum mechanics (QM) partial charges; this technique revealed the molecular rationale behind the observed MAO−B selectivity for this molecular series. Taken together, these results indicate that E7 is a potent, selective and reversible competitive inhibitor of MAO−B with moderately potent AChE inhibitory activity that has potential as a multi‐targeting drug