Premium
Identification of Indole‐Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO‐B Inhibitors
Author(s) -
Sasidharan Rani,
Manju Sreedharannair Leelabaiamma,
Uçar Gülberk,
Baysal Ipek,
Mathew Bijo
Publication year - 2016
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.201600088
Subject(s) - indole test , chemistry , selectivity , monoamine oxidase b , monoamine oxidase , stereochemistry , lead compound , combinatorial chemistry , biochemistry , enzyme , in vitro , catalysis
A series of 11 indole‐based chalcones ( IC1 – 11 ) with various electron donating and withdrawing groups at the para position of the phenyl ring B were synthesized. All the compounds were tested for their human monoamine oxidase (hMAO)‐A and hMAO‐B inhibitory potencies. Most of the synthesized candidates proved to be potent and selective inhibitors of MAO‐B rather than MAO‐A, with a reversible and competitive mode. Among them, compound IC9 was found to be a potent inhibitor of hMAO‐B with K i = 0.01 ± 0.005 μM and a selectivity index of 120. It was found to be better than the standard drug, selegiline (hMAO‐B with K i = 0.20 ± 0.020 μM) with a selectivity index of 30.55. PAMPA assays were carried out for all the compounds in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, IC9 , was nontoxic at 5 and 25 μM, with 95.20 and 69.17% viable cells, respectively. The lead compound IC9 has an antioxidant property of 1.18 Trolox equivalents by ABTS assay. Molecular modeling studies were performed against hMAO‐B to observe binding site interactions of the lead compound.