Synthesis, Molecular Docking, Molecular Dynamics and DFT Studies of New Thiazole Derivatives as Dual Cholinesterase Inhibitors Against Alzheimer’s Disease

While dual cholinesterase (AChE/BChE) inhibitors are urgently needed for Alzheimer’s disease (AD) management, finding effective multi-target agents remains challenging. To address this, we designed and synthesized a novel series of thiazole-bearing compounds and evaluated their dual anticholinesterase and antioxidant potentials. The antioxidant capacities were tested via CUPRAC, FRAP, and DPPH assays, revealing compounds 1 and 8 as the most active derivatives with DPPH IC₅₀ values of 62.510 ± 0.027 μM and 65.190 ± 0.025 μM, respectively]. For ChE inhibition, compound 3 emerged as a highly potent dual competitive inhibitor, outperforming the standard drug donepezil, with IC₅₀ values of 1.440 μM for AChE and 3.620 μM for BChE. In silico studies elucidated the molecular basis of this activity; induced-fit docking revealed strong binding affinities for compound 3 with Glide scores of −9.82 kcal/mol (AChE) and −10.76 kcal/mol (BChE). Subsequent 500 ns molecular dynamics (MD) simulations confirmed the stability of these complexes, exhibiting low average protein RMSD values (2.25 Å for AChE; 2.19 Å for BChE) and highly favorable average MM/GBSA binding free energies (ΔG_bind) of −68.81 kcal/mol and −61.82 kcal/mol, respectively. Additionally, DFT calculations (MEP and FMO) were performed to elucidate the electronic properties correlating with the bioactivity. This study presents a novel thiazole scaffold as a promising lead for developing effective multi-target agents against AD.