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

• Published in: Scientific reports 2024-12, Vol.14 (1), p.31292-17, Article 31292
• Main Authors: Chandran, Namitha, Lee, Jiseong, Prabhakaran, Prabitha, Kumar, Sunil, Sudevan, Sachithra Thazhathuveedu, Parambi, Della Grace Thomas, Alsahli, Tariq G., Pant, Manu, Kim, Hoon, Mathew, Bijo
• Format: Article
• Language: English
• Subjects: 631/154; 631/1647; 631/45; Amine oxidase (flavin-containing); Benzyloxy benzene-based thio/Semicarbazide derivatives; Blood-brain barrier; Blood-Brain Barrier - metabolism; Chemical bonds; Chemistry; Clinical trials; Cytotoxicity; Dialysis; Dopamine; Enzyme kinetics; Glutathione peroxidase; Humanities and Social Sciences; Humans; Hydrocarbons; Hydrogen bonds; Inhibitors; Kinetics; Molecular Docking Simulation; Molecular dynamics; Monoamine oxidase; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; multidisciplinary; Neurodegenerative diseases; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; NMR; Nuclear magnetic resonance; Pharmaceuticals; Pharmacy; Reversibility; Science; Science (multidisciplinary); Semicarbazide; Semicarbazides - chemistry; Semicarbazides - pharmacology; Structure-Activity Relationship; Superoxide Dismutase - antagonists & inhibitors; Superoxide Dismutase - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-82771-3

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 IC 50 value of 0.11 µM against MAO-B, followed by BT6 and BT7 (IC 50  = 0.12 µM) and BT2 (IC 50  = 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 K i 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.