Novel resveratrol-inspired thieno-benzimidazoles and thieno-oxazoles - Synthesis, selective butyrylcholinesterase inhibition and molecular modeling

  • Bioorg Chem. 2026 Jun 17:180:110096. doi: 10.1016/j.bioorg.2026.110096.
Milena Mlakić  1 ,  Stanislava Talić  2 ,  Ilijana Odak  2 ,  Sunčica Roca  3 ,  Ivana Šagud  4 ,  Danijela Barić  5 ,  Irena Škorić  6
Affiliations
  • 1. Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Trg Marka Marulića 19, HR-10 000 Zagreb, Croatia. Electronic address: [email protected].
  • 2. Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice Hrvatske bb, 88 000 Mostar, Bosnia and Herzegovina.
  • 3. NMR Center, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
  • 4. Croatian Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4, HR-10 000, Zagreb, Croatia.
  • 5. Group for Computational Life Sciences, Division of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10 000 Zagreb, Croatia.
  • 6. Department of Organic Chemistry, University of Zagreb Faculty of Chemical Engineering and Technology, Trg Marka Marulića 19, HR-10 000 Zagreb, Croatia. Electronic address: [email protected].
PMID: 42330851 DOI: 10.1016/j.bioorg.2026.110096
Abstract

This study reports the design, synthesis, and biological evaluation of novel resveratrol-inspired thieno-benzimidazole and thieno-oxazole derivatives as potential therapeutics for Alzheimer's disease. The research is grounded in the cholinergic hypothesis, which links cognitive decline to reduced acetylcholine levels due to enzymatic degradation by acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Given the increasing relevance of BChE in later disease stages, the focus was placed on developing selective BChE inhibitors. A series of 14 compounds was synthesized using multi-step organic reactions, including Wittig reactions, Vilsmeier formylation, and cyclization strategies. Structural confirmation was achieved through NMR and mass spectrometry. The studied acetylated derivatives exhibit photochemical instability due to efficient trans-cis isomerization and subsequent secondary processes under UV irradiation, necessitating strict light protection during handling, storage, and application. Biological evaluation revealed that all compounds selectively inhibited BChE, with no significant AChE inhibition observed. Among them, carbamate-oxazole derivative 14 exhibited the highest potency (IC50 = 0.248 μM), outperforming the reference drug rivastigmine. Several Other derivatives showed moderate to strong activity, with oxazole-based compounds generally outperforming benzimidazole analogs. In addition to enzyme inhibition, antioxidant activity was assessed using the DPPH and CUPRAC assays. Compound 8 exhibited the strongest radical-scavenging activity, comparable to that of Trolox. Molecular docking and dynamics simulations provided insight into binding interactions, highlighting key π-π stacking and hydrogen bonding within the BChE active site. Furthermore, in silico genotoxicity analysis indicated that the most active compounds lack mutagenic potential. Overall, the study identifies promising multifunctional candidates combining selective BChE inhibition, antioxidant properties, and favorable safety profiles, supporting their potential as lead compounds for Alzheimer's disease therapy.

Keywords
Antioxidative activity; Benzimidazoles; Butyrylcholinesterase inhibition; Design; Diarylethenes, docking study; Oxazoles; Resveratrol analogues.
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