Mlakic_2026_Bioorg.Chem_180_110096

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 (IC(50) = 0.248 microM), 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 Pi-Pi 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.