2. Academic Validation
  3. New class of thio/semicarbazide-based benzyloxy derivatives as selective class of monoamine oxidase-B inhibitors

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

  • Sci Rep. 2024 Dec 28;14(1):31292. doi: 10.1038/s41598-024-82771-3.
Namitha Chandran # 1,  Jiseong Lee # 2,  Prabitha Prabhakaran 3,  Sunil Kumar 1,  Sachithra Thazhathuveedu Sudevan 1,  Della Grace Thomas Parambi 4,  Tariq G Alsahli 5,  Manu Pant 6,  Hoon Kim 7,  Bijo Mathew 8
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, India.
  • 2 Department of Pharmacy, College of Pharmacy, Sunchon National University, Suncheon, 57922, Republic of Korea.
  • 3 Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Mysuru, Mysuru, 570015, India.
  • 4 Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia.
  • 5 Department of Pharmacology, College of Pharmacy, Jouf University, 72341, Sakaka, Aljouf, Saudi Arabia.
  • 6 Department of Biotechnology, Graphic Era (Deemed to be university), Clement town, Dehradun, 248002, India.
  • 7 Department of Pharmacy, College of Pharmacy, Sunchon National University, Suncheon, 57922, Republic of Korea. hoon@sunchon.ac.kr.
  • 8 Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682041, India. bijomathew@aims.amrita.edu.
  • # Contributed equally.
PMID: 39732801 DOI: 10.1038/s41598-024-82771-3
Abstract

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.

Keywords

Benzyloxy benzene-based thio/Semicarbazide derivatives; Kinetics; Molecular dynamics; Monoamine oxidase; Reversibility.

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