Montargil_2025_Bioorg.Med.Chem_131_118419

Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60-70 % of cases. beta-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid beta. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules - some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules 12a underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (3a, 3b, 3i and 12a) have shown moderate BuChE inhibitory activity.