Exploring the potential of new acetylated unsaturated Oxindole derivatives as multi-target inhibitors for BACE1 and BuChE
Catarina A Montargil, Mariana Pinto, Rosa Resende, Elisabete P. Carreiro, Alfonso T. García‐Sosa, Armanda E. Santos, Anthony Joseph Burke · Bioorganic & Medicinal Chemistry · 2025
Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60–70 % of cases. β-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 β. 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 underwent cytotoxicity and antioxidant screens 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). In addition, some of the other compounds were shown to be moderate BuChE inhibitors, and four of these compounds were bone-fide multi-targeting inhibitors. • The development of New Multi-target inhibitors for two important Alzheimer's disease targets, namely, β-Secretase (BACE1), Acetylcholinesterase and Butyrlcholinesterase (BuChE). • Expansion of the chemical space of oxindoles with the synthesis of novel hydroxy and acyl oxindoles bearing benzyl and olefin containing pharmacophore units in both the 3 and N-position of the ring. • New fluorinated oxindoles for enhanced biological activity. • 27 compounds were synthesized, characterized and then bioassayed. • The relatively under-utilized Indium mediated Barbier coupling reaction was investigated, proving more efficient that the equivalent Grignard reaction. • The compounds were screened against, BACE-1, and 4 of these compounds showed good inhibitions. • Both 3 h and 12a was subjected to docking studies, and showed better binding than the experimental clinical trial drug AZD3293 (Lanabecestat).