Novel adenine-based hybrids bearing thiosemicarbazide, thiadiazole, and coumarin scaffolds: Design, synthesis, molecular docking-supported AChE inhibitory activity
Journal of Molecular Structure, vol.1378, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 1378
- Publication Date: 2026
- Doi Number: 10.1016/j.molstruc.2026.147285
- Journal Name: Journal of Molecular Structure
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Keywords: Acetylcholinesterase, Adenine, Coumarin, Molecular docking, Thiadiazole
- Recep Tayyip Erdoğan University Affiliated: Yes
Abstract
In this study, novel adenine-based hybrid compounds containing thiosemicarbazide, thiadiazole, and coumarin scaffolds were synthesized. The acetylcholinesterase (AChE) inhibitory activities of these compounds were subsequently evaluated. While almost all thiadiazole derivatives exhibited inhibitory activity, the most potent compound was N'-(2-(6-amino-9H-purin-9-yl)acetyl)-2-oxo-2H-chromene-3-carbohydrazide (5a), with an IC₅₀ value of 12.66 ± 0.05 µg/mL. Comprehensive in silico analyses, including molecular docking, 100 ns molecular dynamics (MD) simulations, and MM-GBSA binding free energy calculations, demonstrated that compound 5a exhibits a highly stable dual-binding mode by interacting simultaneously with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. These findings highlight this sterically unhindered hybrid scaffold as a promising lead structure for the rational design of next-generation AChE inhibitors.