Nadur_2025_Pharmaceuticals.(Basel)_18_1398

Background: Multitarget-directed ligands (MTDLs), particularly those combining cholinesterase inhibition with additional mechanisms, are promising candidates for Alzheimer's disease (AD) therapy. Based on our previous identification of a dual-active coumarin derivative, we designed a new series of 7-alkoxyamino-3-(1,2,3-triazole)-coumarins. Methods: These compounds were synthesized by a new Sonogashira protocol and evaluated for AChE and BChE inhibition, enzymatic kinetics, molecular docking, neurotoxicity in SH-SY5Y cells, neuroprotection against H(2)O(2)-induced oxidative stress, and additional interactions with H(3)R and MAOs. Results: All derivatives inhibited AChE with IC(50) values of 4-104 nM, displaying high selectivity over BChE (up to 686-fold). Kinetic and docking studies indicated mixed-type inhibition involving both CAS and PAS. The most potent compounds (1h, 1j, 1k, 1q) were non-neurotoxic up to 50 microM, while 1h and 1k also showed neuroprotective effects at 12.5 microM. Selected derivatives (1b, 1h, 1q) demonstrated multitarget potential, including H(3)R affinity (K(i) as low as 32 nM for 1b) and MAO inhibition (IC(50) of 1688 nM for 1q). Conclusions: This series of coumarin-triazole derivatives combines potent and selective AChE inhibition with neuroprotective and multitarget activities, highlighting their promise as candidates for AD therapy.