β-Maltose-conjugated acetophenone thiosemicarbazones as multitarget inhibitors of diabetes- and Alzheimer's disease-related enzymes: Design, synthesis, and mechanistic evaluation.

This study describes the design, synthesis, and biological evaluation of a series of β-maltose-conjugated acetophenone thiosemicarbazones (6a-p) as multitarget inhibitors against enzymes associated with Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). The synthesized compounds were evaluated for their inhibitory activities against α-amylase, α-glucosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The biological results demonstrated that the nature and position of substituents on the phenyl ring strongly influenced both potency and selectivity. Among the tested compounds, derivative 6 m emerged as the most promising multitarget inhibitor, exhibiting potent α-glucosidase inhibition (IC50 = 6.75 μM), superior to the reference drug acarbose, together with remarkable selectivity toward BChE (IC50 = 0.035 μM). Compound 6 k displayed balanced inhibitory activity, showing potent AChE inhibition (IC50 = 0.045 μM), comparable to donepezil, while retaining significant antidiabetic activity. Structure-activity relationship (SAR) analysis revealed that hydroxyl substituents were crucial for antidiabetic activity, whereas halogen substitution markedly enhanced cholinesterase inhibition. Kinetic studies demonstrated that the most active compounds acted as competitive inhibitors. Furthermore, molecular docking and molecular dynamics simulations confirmed stable binding interactions within the catalytic pockets of the target enzymes through hydrogen bonding, hydrophobic interactions, and interactions with catalytic and anionic residues. Overall, these findings identify β-maltose-conjugated thiosemicarbazones as promising multitarget-directed ligands for the development of therapeutic agents against metabolic and neurodegenerative disorders.