Structure-Guided Optimization of 1,2,4-Triazole-Thione-Based Mannich Derivatives as Dual-Target Modulators:...

Area of Science:

• Neuroscience
• Medicinal Chemistry

Background:

• Neurotransmitter imbalances are implicated in neurodegenerative diseases like Alzheimer's disease (AD).
• Current AD treatment strategies are shifting towards multi-target approaches, focusing on dual-acting inhibitors.

Purpose of the Study:

• To synthesize and evaluate novel compounds as dual inhibitors of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) for potential AD therapy.
• To investigate the inhibitory profiles of synthesized compounds against AChE, BChE, MAO-A, and MAO-B.

Main Methods:

• Synthesis of 10 new compounds (5a-j) featuring a phenolic ring, amine tail, and 1,2,4-triazole core.
• In vitro enzyme inhibition assays to determine IC50 values for AChE, BChE, MAO-A, and MAO-B.
• In silico molecular docking studies to assess interactions with human AChE (hAChE) and human MAO-B (hMAO-B).

Main Results:

• Compound 5b demonstrated potent dual inhibitory activity against AChE (IC50 = 0.136 ± 0.006 μM) and MAO-B (IC50 = 0.108 ± 0.005 μM).
• Docking studies confirmed that compound 5b interacts with key amino acid residues in the active sites of hAChE and hMAO-B.
• Compounds 5a-j were synthesized and their cholinesterase and MAO inhibitory profiles were characterized.

Conclusions:

• Compound 5b is a promising dual-target inhibitor of AChE and MAO-B.
• The findings suggest compound 5b as a potential therapeutic candidate for Alzheimer's disease treatment.