Yu_2025_Bioorg.Chem_161_108478

In our recent investigation, we conducted a systematic search for novel L-Tryptophan derivatives exhibiting marked inhibitory effects against human serum butyrylcholinesterase (hBuChE), an enzyme intricately implicated in the pathological cascade of Alzheimer's Disease (AD). Two lead compounds among these derivatives, Z165 and Z168 displayed IC(50) values of 0.44 microM and 3.23 microM against butyrylcholinesterase, suggesting their promising potential for further structural optimization. Chemical modifications were subsequently undertaken to enhance the inhibitory activities of these leads, culminating in the development of compounds 4d-9, 4d-12, and 4d-13, which demonstrated IC(50) values of 0.29 microM, 0.52 microM, and 0.13 microM, respectively. Furthermore, the following investigation revealed that these compounds exhibit exceptional antioxidant properties when juxtaposed with ascorbic acid. They are also proficient in inhibiting the aggregation of amyloid-beta (Abeta) peptides while concurrently displaying minimal cytotoxic effects towards BV-2 cell lines. Meanwhile the good blood-brain barrier permeability of these compounds was confirmed in PAMPA-BBB assay. Remarkably, compound 4d-13, which demonstrated the most potent inhibitory activity against butyrylcholinesterase, also afforded consistent neuroprotective effects compared with Galantamine against the injury induced by NMDA or L-(+)-Sodium glutamate in SH-SY5Y cells. Besides, 4d-13 could reduce the expression of inflammatory factors IL-1beta and IL-6 dose-dependently in the LPS induced BV-2 inflammatory model. Morris water maze and step-down testing in vivo confirmed that 4d-13 could ameliorate scopolamine-induced cognitive deficits. These findings suggest that these compounds are promising leads for the development of therapeutic agents against AD.