Advances in 1,3,4-thiadiazole-based cholinesterase inhibitors: toward novel therapeutics for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which cholinergic dysfunction plays a central role. Inhibition of acetylcholinesterase and butyrylcholinesterase remains a validated therapeutic approach for managing AD symptoms. Over the past decade (2015-2025), 1,3,4-thiadiazole derivatives have gained considerable attention as promising scaffolds for cholinesterase inhibition owing to their favorable electronic configuration, hydrogen-bonding potential, and metabolic stability. This review comprehensively analyzes recent progress in the synthesis and biological evaluation of 1,3,4-thiadiazole-based cholinesterase inhibitors, with an emphasis on structure-activity relationship trends supported by molecular docking insights. Substitution with electron-withdrawing or heteroaryl groups has been found to enhance the binding affinity toward AChE and BuChE, while some derivatives also exhibit activity against carbonic anhydrase, α-glucosidase, α-amylase, and antioxidant systems, reflecting scaffold versatility. This review further highlights the docking interactions with catalytic residues that validate the observed experimental potency. Finally, key limitations and future directions are discussed, emphasizing rational structure modification, computationally guided design, and green synthetic approaches to develop brain-penetrant and pharmacologically optimized 1,3,4-thiadiazole-based anti-Alzheimer's agents.