From bench to brain: novel thieno-oxazine hybrids as potent pleiotropic anti-Alzheimer's agents with in vivo/ in vitro validation and in silico insights

  • J Enzyme Inhib Med Chem. 2026 Dec;41(1):2598741. doi: 10.1080/14756366.2025.2598741.
Eman A Fayed  1 ,  Mazin A A Najm  2 ,  Khulood H Oudah  2 ,  Maha A Ebrahim  1 ,  Nirvana A Gohar  3 ,  Karema Abu-Elfotuh  4  5 ,  Ehsan Khedre Mohamed  6 ,  Ahmed M E Hamdan  7  8 ,  Najla A Albalawi  9 ,  Shahad Faisal Alzahrani  9 ,  Amira M Hamdan  10 ,  Reema Almotairi  8  11 ,  Shaimaa M Hafez  12 ,  Triveena M Ramsis  13
Affiliations
  • 1. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
  • 2. Department of Pharmacy, Mazaya University College, Nasiriyah, Iraq.
  • 3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, Egypt.
  • 4. Department of Clinical Pharmacy, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
  • 5. College of Pharmacy, Al-Ayen Iraqi University, Thi-Qar, Iraq.
  • 6. Department of Biochemistry, Egyptian Drug Authority (EDA), formerly National Organization of Drug Control and Research (NODCAR), Giza, Egypt.
  • 7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
  • 8. Prince Fahad Bin Sultan Chair for Biomedical Research (PFSCBR), University of Tabuk, Tabuk, Saudi Arabia.
  • 9. Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.
  • 10. Oceanography Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
  • 11. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia.
  • 12. Department of Anatomy and Embryology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt.
  • 13. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University, Ismailia, Egypt.
PMID: 41481412 DOI: 10.1080/14756366.2025.2598741
Abstract

Due to their various pharmacological effects, several substituted sulphur heterocycles containing thiophene have recently attracted a great deal of attention. A novel 2,3-diaryl-2,3,5,6,7,8-hexahydro-4H-benzo[4,5]thieno[3,2-e][1,3]oxazin-4-one (9-14) was synthesised starting from cyclohexa[b]thiophene. Compounds 9 and 10 showed the greatest gene expression downregulation of Bax by 75.1% and 79.7%, and upregulation of Bcl-2 gene expression by 8.1 folds for each. It also decreased the level of AChE by 70.2 and 75%; respectively. Compounds 9 and 10 significantly increased Wnt3a levels by 5.8 and 6.6 folds, and β-catenin levels by 10.1 and 10.5 folds, respectively, compared to donepezil. They significantly downregulated 5-GSK3β gene expression by 77.1%, and 78.7%, respectively. Even though all compounds exhibited potent inhibition of AChE, all synthesised compounds, except for compounds 5 and 11 demonstrated higher selectivity towards BChE (SI < 1). In-silico ADMET calculations as well as molecular docking have been performed for synthetic compounds.

Keywords
AChE and BChE inhibitors; ADMET and docking studies; Alzheimer’s disease; Thieno-oxazines; multi-targets and histopathological examinations.
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