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 <b>8</b> (IC₅₀ = 0.117 μM) and <b>14</b> (IC₅₀ = 0.092 μM) showed superior activity against AChE than reference tacrine (IC₅₀ = 0.274 μM), while compound <b>13</b> (IC₅₀ = 5.35 μM) showed comparable potency against BACE1 to quercetin (IC₅₀ = 4.89 μM). Nevertheless, compounds <b>3</b> and <b>9</b> were the most active among the series against BChE. Interestingly, compounds <b>8</b>, <b>13</b>, and <b>14</b> 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 <b>8</b>, <b>13</b>, and <b>14</b> showed BACE1 binding affinities similar to quercetin. On the other hand, compounds <b>3</b>, <b>11</b>, and <b>14</b> displayed comparable binding conformations to donepezil. Further molecular dynamics simulations revealed stabilization of <b>8</b>, <b>13</b>, and <b>14</b> complexes inside BACE1, while derivatives <b>3</b>, <b>11</b>, and <b>14</b> showed stabilizing effects on BChE compared to the apoenzyme. <i>In silico</i> 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.