Novel thiadiazole derivatives targeting acetylcholinesterase in Alzheimer’s disease: Synthesis and biological evaluation

Acetylcholine levels are decreased frequently linked to Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive impairment, as a result of increased acetylcholinesterase (AChE) activity.Several new thiadiazole compounds were synthesized for this investigation, and their potential as neuroprotective and AChE inhibitors was evaluated.The synthetic route involved the initial formation of 2-(5-amino-1,3,4-thiadiazol-2-yl)-5-bromophenol using thiosemicarbazide and 4-bromo salicylic acid, followed by Schiff base condensation with various substituted aromatic and heteroaromatic aldehydes.All compounds were structurally characterized by IR,¹H and C13NMR, and mass spectroscopy and confirmed for purity.Molecular docking studies against acetylcholinesterase (PDB ID: 4EY6) revealed strong binding affinities, particularly for compound T3 [(E)-2-(5-((4-aminobenzylidene)amino)-1,3,4-thiadiazol-2-yl)-5-bromophenol], which exhibited notable hydrogen bonding and hydrophobic interactions at the AChE active site.In vitro MTT assays on neuronal cells demonstrated that T3 significantly enhanced cell viability, indicating potent neuroprotective activity with low cytotoxicity, even outperforming the standard drug used as a reference.The novelty of this work lies in the strategic integration of pharmacologically active moieties within a single molecular scaffold, offering dual benefits of AChE inhibition and neuroprotection.Additionally, efforts to minimize toxicity through molecular design, and early-stage biological screening underscore the compound's promise as a safe therapeutic candidate for AD.These results provide support for the potential of derivatives based on thiadiazole in the creation of strong medications that target neur o degenerative illnesses.