Development of 1-(substituted benzofuran-2-yl)-3-(halogen-substituted phenyl)prop-2-en-1-ones as potent, reversible, and selective MAO-B inhibitors for Parkinson's Disease

  • Sci Rep. 2026 Jun 3. doi: 10.1038/s41598-026-53367-w.
Ali Hasan  1 ,  Jiseong Lee  #  2 ,  Naresh Payyaula  #  1 ,  Vishnu Vasanthi Radhakrishanan  1 ,  Sachithra Thazhathuveedu Sudevan  1 ,  Sunil Kumar  1 ,  Della Grace Thomas Parambi  3 ,  Kasim Sakran Abass  4 ,  Arun Kumar  5 ,  Naseer Maliyakkal  6 ,  Hoon Kim  7 ,  Bijo Mathew  8
Affiliations
  • 1. Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India.
  • 2. Department of Pharmacy, College of Pharmacy, SunchonNational University, Suncheon, 57922, Republic of Korea.
  • 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jouf University, Sakaka Al Jouf, 72341, Saudi Arabia.
  • 4. Department of Physiology, Biochemistry, and Pharmacology, College of Veterinary Medicine, University of Kirkuk, Kirkuk, 36001, Iraq.
  • 5. School of Pharmacy, Sharda University, Knowledge Park III, Greater Noida, India.
  • 6. Department of Anesthesia and Operations, College of Applied Medical Sciences, King Khalid University, Khamis Mushait, Kingdom of Saudi Arabia.
  • 7. Department of Pharmacy, College of Pharmacy, SunchonNational University, Suncheon, 57922, Republic of Korea. [email protected].
  • 8. Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi, 682 041, India. [email protected].
  • # Contributed equally.
PMID: 42230935 DOI: 10.1038/s41598-026-53367-w
Abstract

Ten halogenated benzofuran derivatives (BF1-BF10) were synthesized and evaluated for their inhibitory activity against Monoamine Oxidase isoforms. All compounds showed stronger inhibition of MAO-B compared to MAO-A. Among them, BF2 exhibited the most potent MAO-B inhibition (IC₅₀ = 0.082 µM), followed by BF5 (IC₅₀ = 0.095 µM) and BF1 (IC₅₀ = 0.16 µM), with high selectivity indices, particularly BF2 (SI = 1038.05). Kinetic studies revealed that BF2 acts as a competitive inhibitor with a Ki value of 0.083 ± 0.0056 µM. Dialysis experiments confirmed its reversible inhibition profile, comparable to the reference drug Safinamide. Both BF2and BF5 were non-cytotoxic toward L929 cells and demonstrated moderate blood-brain barrier permeability in PAMPA assay. Molecular docking showed stabilization of MAO-B via π-π stacking interactions with Tyr326 and Tyr398, and molecular dynamics simulations further confirmed stable binding of BF2 within the MAO-B active site. Overall, BF2 emerged as a potent, selective, and reversible MAO-B Inhibitor, warranting for further investigation.

Keywords
Benzofuran; Chalcone; Kinetics; MAO-B; Molecular docking; Reversibility.
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