New class of thio/semicarbazide�based benzyloxy derivatives as selective class of monoamine oxidase-B inhibitors

Sixteen thio/semicarbazide-based benzyloxy derivatives (BT1-BT16) were synthesized and evaluated
for their inhibitory activities against monoamine oxidases (MAOs). Most compounds showed better
inhibitory activity against MAO-B than against MAO-A. BT1, BT3, and BT5 showed the greatest
inhibitory activity with an identical IC50 value of 0.11 µM against MAO-B, followed by BT6 and BT7
(IC50 = 0.12 µM) and BT2 (IC50 = 1.68 µM). The selectivity index of BT5 was the highest (363.64) for
MAO-B, whereas that of BT1 was 88.73. BT1 and BT5 were reversible MAO-B inhibitors, based on
the results of dialysis experiments. In inhibition kinetics, BT1 and BT5 were competitive MAO-B
inhibitors with Ki
values of 0.074 ± 0.0020 and 0.072 ± 0.0079 µM, respectively. Additionally, in the
in-vitro parallel artificial membrane penetration assay, BT1 and BT5 crossed the blood–brain barrier.
Cytotoxicity and possible neuroprotective effects of the lead compounds were assessed using IMR 32
cells. Levels of the antioxidant superoxide dismutase, catalase, and glutathione peroxidase in IMR 32
cells were increased by pretreatment with lead compounds. Five lead molecules (BT1, BT3, BT5, BT6,
and BT7) were used for the docking studies. A significant pi–pi interaction with Tyr 326 was observed
and molecular dynamics studies were performed for the most promising BT1-MAO-B complex.
These results suggested that BT1 and BT5 could be used therapeutically for the treatment of various
neurodegenerative diseases.