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  3. Coumarin-Chalcone derivatives as promising antioxidant agents targeting ischemia/reperfusion injury through Nrf2 pathway activation

Coumarin-Chalcone derivatives as promising antioxidant agents targeting ischemia/reperfusion injury through Nrf2 pathway activation

  • Bioorg Chem. 2025 Jul 26:164:108790. doi: 10.1016/j.bioorg.2025.108790.
Maryam Mohammadnia 1,  Zahra Emamgholipour 2,  Fariba Peytam 3,  Marjan Nikbakhtzadeh 4,  Saereh Hosseindoost 5,  Salwa Basheer Alsaeed 6,  Fardin Sehati 7,  Mohsen Shahba 8,  Hamid Reza Bijanzadeh 9,  Hayrettin Ozan Gulcan 10,  Loghman Firoozpour 2,  Fahimeh Ghasemi 11,  Ghorbangol Ashabi 12,  Alireza Foroumadi 13
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 3 Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5 Pain Research Center, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, International Campus, Tehran University of Medical Sciences, Tehran, Iran.
  • 7 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • 8 Department of Neurosurgery, Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
  • 9 Department of Environmental Sciences, Faculty of Natural Resources and Marine Sciences, Tarbiat Modares University, Tehran, Iran.
  • 10 Faculty of Pharmacy, Eastern Mediterranean University, via Mersin 10, Famagusta, TRNC, Turkey.
  • 11 Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • 12 Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran. Electronic address: gh-ashabi@tums.ac.ir.
  • 13 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran; Department of Medicinal Chemistry, School of Pharmacy, International Campus, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: aforoumadi@yahoo.com.
PMID: 40743708 DOI: 10.1016/j.bioorg.2025.108790
Abstract

Ischemic stroke remains a major global cause of mortality. Reperfusion therapy with thrombolysis paradoxically raises Reactive Oxygen Species (ROS) and causes cerebral ischemia-reperfusion injury (CIRI). To address this challenge, Antioxidants, which directly neutralize ROS or indirectly activate the KEAP1/Nrf2/ARE pathway, have emerged as promising strategies. Given the antioxidant properties of natural Coumarins and Chalcones, we designed and synthesized coumarin-chalcone analogs to assess their neuroprotective potential against CIRI by activating the Nrf2 pathway. Interestingly, the in vitro H2O2-induced oxidative stress model demonstrated that compounds 7f, 7j, and 7l significantly enhanced the viability of hippocampal neuronal cells following H2O2 exposure. Further in vivo evaluation of 7l using the 2VO cerebral hypoperfusion model demonstrated improvements in motor function, sensory response, memory, and hippocampal neuronal preservation. Furthermore, molecular docking and molecular dynamics simulations confirmed the stable binding of 7l compound in the Keap1 Kelch domain. It warrants its ability to disrupt Keap1-Nrf2 interactions and activate antioxidant defense mechanisms. This was confirmed biochemically by increased expression of Nrf2, SOD, and CAT, along with reduced malondialdehyde levels in the treated group. Overall, these results highlight compound 7l as a promising neuroprotective candidate for combating CIRI through antioxidant and Nrf2-mediated mechanisms.

Keywords

Antioxidant; Coumarin-chalcone derivatives; Ischemia/reperfusion injury; Keap1; Neuroprotective; Nrf2.

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