Arylboronic Acid Derivatives as Multi-Target Directed Ligands for Alzheimer’s Disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder involving cholinergic dysfunction, oxidative stress, neuroinflammation, and β-amyloid accumulation. Boronic compounds have been emerging in drug discovery by nucleophilic interactions with residues of enzyme active sites. Given this potential, 17 derivatives were evaluated as multi-target directed ligands (MTDL) for AD, targeting acetylcholinesterase (AChE), butyrylcholinesterase (BChE), myeloperoxidase (MPO), monoamine oxidase B (MAO−B), and β-secretase (BACE−1). AChE/BChE inhibition were evaluated by Ellman’s method. MPO chlorination/peroxidase inhibition by HOCl formation and TMB oxidation, respectively. MAO-A/B inhibition by peroxidase linked assay, while BACE−1 using commercial kit. Derivatives with >80% inhibition in screening had IC₅₀ values determined and expressed as mean ± standard error of the mean. Docking validation used redocking, multiple scoring functions, and binding site radius (BChE: W82, 20 Å; MPO: H95, 10 Å; BACE-1: D32, 20 Å). ChemPLP, ChemScore, and GoldScore yielded RMSDs of 0.40 Å (BChE), 0.52 Å (MPO), and 0.44 Å (BACE-1), confirming the co-crystallized poses. Derivatives NO-01, 03, 09, 13, 82, 86, and 91 showed a MTDL profile by inhibiting BChE (IC₅₀: 24.8±1, 19.1±1.6, 58.7±1.6, 0.3±0.1, 0.1±0.04, 46.7±13.8, and 4.4±2.1 µM, respectively) and MPO chlorination (14±1, 31.9±3.2, 2.2±0.3, 46.2±2.3, 24.7±1.3, 10.7±0.5, and 44.1±6.1 µM, respectively). Among these, NO-01, 03, 13, 86, and 91 also inhibited MPO peroxidase (36.5±3.1, 33.8±7.7, 37.9±9.3, 21±5.2, and 57.6±9.3 µM, respectively). NO-13 further inhibited BACE-1 (65.1±1.2 µM), while NO-134 inhibited MPO chlorination (44.9±7 µM), peroxidase (37.6±4.6 µM), and MAO-B (1.9±0.4 µM). Several derivatives showed a MTDL profile, notably NO-13, which inhibited BChE, MPO activities, and BACE-1. Molecular docking indicated boronic acid interactions with key catalytic residues, supporting its potential to modulate multiple AD-related pathways.