Synthesis‐Oriented Molecular Frameworks of Novel Pyrimidine–Thiadiazole Derivatives: Kinetic Behavior, Binding Mechanism, and Pharmacological Investigations Targeting Alzheimer's Disease

Abstract The present study focuses on synthesis of pyrimidine derived thiadiazole based Schiff base derivatives (1–10), as effective inhibitors against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) for treatment of Alzheimer's disease. Among these analogs, strong inhibition was shown by analog 8 with IC 50 of 2.70 ± 0.30 µM for AChE as well as 3.10 ± 0.20 µM for BChE, and analog 4 with IC 50 of 4.30 ± 0.20 µM for AChE as well as 4.80 ± 0.10 µM for BChE indicating potent inhibition for antidementia agents relative to the reference drug donepezil. Similarly, other analogues also exhibited an improved inhibition profile against both these targeted enzymes. Structure activity correlation was established based on quantity, type, location, and electron donative/accepting effects of substitution/s on benzene rings. Using in silico approaches, including molecular docking, density functional theory, and ADMET analysis were employed to investigate the binding affinities, reactivity, molecular stability, and kinetic behavior of promising analogs. By using HREI‐MS, 1 H NMR, and 13 C NMR spectroscopy, structures of newly reported analogues were confirmed.