Repurposed Arylidene-hydrazinyl-1,3-thiazoles as Multitarget Anti-Alzheimer's Agents via Combined Computational and Experimental Studies.

In quest of new and potent multitarget therapeutics for Alzheimer's disease (AD), a series of recently synthesized arylidene-hydrazinyl-thiazoles were repurposed as multitarget directed anti-AD agents. In total, 14 compounds were tested for their inhibitory activities against the key enzymes acetylcholinesterase (AChE), β-secretase 1 (BACE1), and butyrylcholinesterase (BChE). Derivatives 8 (IC50 = 0.117 μM) and 14 (IC50 = 0.092 μM) showed superior activity against AChE than reference tacrine (IC50 = 0.274 μM), while compound 13 (IC50 = 5.35 μM) showed comparable potency against BACE1 to quercetin (IC50 = 4.89 μM). Nevertheless, compounds 3 and 9 were the most active among the series against BChE. Interestingly, compounds 8, 13, and 14 were considered multitarget ligands against both AChE and BACE1 enzymes. A variable window molecular docking study revealed favorable binding affinities for the thiazole ligands, confirmed by the low ligand-protein binding energies, toward BACE1 and BChE rather than AChE. Compounds 8, 13, and 14 showed BACE1 binding affinities similar to quercetin. On the other hand, compounds 3, 11, and 14 displayed comparable binding conformations to donepezil. Further molecular dynamics simulations revealed stabilization of 8, 13, and 14 complexes inside BACE1, while derivatives 3, 11, and 14 showed stabilizing effects on BChE compared to the apoenzyme. In silico ADMET profiling highlighted the appropriate drug-like properties of the thiazole ligands, which possessed low toxic effects and good pharmacokinetic properties. Overall, the multitarget profile exerted by our thiazole ligands suggests their potential qualification as anti-Alzheimer candidates in AD therapy.