Design, Synthesis, and Biological Evaluation of Novel Multitarget 7-Alcoxyamino-3-(1,2,3-triazole)-coumarins as Potent Acetylcholinesterase Inhibitors

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 µM, while 1h and 1k also showed neuroprotective effects at 12.5 µM. 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.