STRUCTURE-GUIDED INVESTIGATION OF BENZOTHIAZOLE DERIVATIVES FOR ALZHEIMER'S DISEASE: COMBINING MOLECULAR DOCKING AND IN-VITRO RESEARCH

Multiple pathological mechanisms, including cholinergic dysfunction, amyloid-beta (A) aggregation, oxidative stress, and neuroinflammation, contribute to Alzheimer's disease (AD), a multifactorial neurodegenerative disorder marked by progressive cognitive decline and memory loss.The conventional "one-target, one-drug" strategy has proven ineffective due to the complexity of AD pathology.As a result, multi-target-directed ligands, or MTDLs, have become a viable therapeutic approach.Because of their structural adaptability and capacity to interact with a variety of biological targets pertinent to AD, benzothiazole-based compounds have attracted a lot of attention.Recent developments demonstrate that benzothiazole derivatives are not only strong inhibitors of acetylcholinesterase (AChE) but also modulators of monoamine oxidase B (MAO-B), butyrylcholinesterase (BuChE), and A1-42 aggregation.Some compounds also target the histamine H3 receptor (H3R).Compounds with strong binding affinities toward both AChE and A1-42 have been identified by in silico studies on benzothiazole-isothiourea hybrids, outperforming reference molecules such as curcumin and galantamine.Despite having limited blood-brain barrier permeability, compound 3t emerged as a lead candidate due to its favorable drug-likeness profile and low cytotoxicity, which were confirmed by in vitro assays.The potential of benzothiazole scaffolds as a basis for the creation of novel, multitarget therapeutic agents against AD is further supported by these findings.