Identification of Indole-Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors

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• 作者：Rani Sasidharan ; Sreedharannair Leelabaiamma Manju ; Gü ; lberk Uç ; ar ; Ipek Baysal and Bijo Mathew
• 刊名：Archiv der Pharmazie
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：349
• 期：8
• 页码：627-637
• 全文大小：855K
• ISSN：1521-4184

文摘

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.