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

Diseases such as Alzheimer's, Parkinson's, and depression result from neurotransmitter imbalances. In particular, for AD, it is critical to inhibit AChE to preserve the decline in acetylcholine levels and to block excessive MAO-B activity, which leads to nerve damage and cognitive impairment. As current scientific research has moved away from the "one drug for one target" approach toward a "multi-target" strategy, dual-acting inhibitors that simultaneously inhibit both AChE and MAO-B enzymes are considered the most promising new drug candidates for the treatment of Alzheimer's disease. In this study, we investigated the inhibition of AChE, BChE, MAO-A, and MAO-B in the pathophysiology of AD as a working group. Within the scope, 10 new compounds (5a-j) were synthesized, consisting of a phenolic ring, a secondary or tertiary amine tail, and a 1,2,4-triazole core. The cholinesterase and MAO inhibitory profiles of the compounds were investigated using both in vitro and in silico methods. Compound 5b exhibited dual inhibitory activity against AChE and MAO-B enzymes, with IC₅₀ values of 0.136 ± 0.006 μM and 0.108 ± 0.005 μM, respectively. In accordance with 5b, it interacted with crucial amino acids of the hAChE and hMAO-B enzymes in the docking studies. These results suggest that 5b is a dual-target inhibitor of AChE and MAO-B and represents a promising therapeutic option for the treatment of Alzheimer's disease.