Coumarin 1,3,4-thiadiazole derivatives: Synthesis, bioactivity, and In Silico evaluation as Alzheimer's Disease inhibitors

This study reports the synthesis of a new series of asymmetric coumarin–1,3,4-thiadiazole derivatives (T1a–T1g, T2a–T2c, T3a–T3b) targeting biochemical pathways relevant to Alzheimer's disease. Three coumarin precursors (C1–C3) were employed, using a one-pot sequential addition followed by alkylation to afford alkylated coumarin intermediates. Subsequent condensation with thiosemicarbazide under mild basic conditions and intramolecular cyclization yielded previously unreported asymmetric coumarin–thiadiazole derivatives. Twelve compounds were obtained in high yields (>82%) and fully characterized by 1H and 13C NMR spectroscopy. Biological evaluation revealed significant antioxidant and anti-acetylcholinesterase (AChE) activities, supported by In Silico analyses. In the ABTS assay, compounds T1a, T1b, T1c, T1d, T1f, and T2b exhibited strong radical scavenging activity (IC₅₀ = 24.32 ± 0.32–50.14 ± 0.17 μM), comparable to BHT (47.84 ± 0.22 μM). Phenanthroline reduction identified T1f, T3a, and T1d as the most potent reducing agents (A₀.₅ = 11.38–31.90 μM), approaching BHA (7.32 ± 0.83 μM). AChE inhibition was most pronounced for T1f and T1g (IC₅₀ = 38.90 ± 0.46 and 20.35 ± 0.06 μM, respectively), relative to galantamine (IC₅₀ = 4.14 ± 0.07 μM). Molecular docking confirmed strong binding within the AChE active site, while quantum chemical and ADMET analyses indicated favorable electronic properties, electron-donating substituent effects, and drug-like pharmacokinetic profiles. T1f, T1g, T1c, and T3a emerged as multifunctional lead candidates combining antioxidant and AChE inhibitory activities, highlighting the coumarin–thiadiazole scaffold as a promising platform for the development of therapeutics targeting oxidative stress-associated neurodegenerative disorders.