Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations.

Nine compounds (MO1-MO9) containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; MO1 most potently inhibited with an IC50 value of 0.030 µM, followed by MO7 (0.25 µM). MO5 most potently inhibited AChE (IC50 = 6.1 µM), followed by MO9 (IC50 = 12.01 µM) and MO7 most potently inhibited MAO-A (IC50 = 7.1 µM). MO1 was a reversible mixed-type inhibitor of MAO-B (Ki = 0.018 µM); MO5 reversibly competitively inhibited AChE (Ki = 2.52 µM); and MO9 reversibly noncompetitively inhibited AChE (Ki = 7.04 µM). MO1, MO5 and MO9 crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that MO1 is a selective inhibitor of MAO-B and that MO5 is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.

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

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 Ki = 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 Ki = 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.