The grinding technique is a mechanochemical method that avoids the use of solvents in the reaction mixture, thereby reducing the detrimental effects of vapour and affording an environmentally and economically efficient process. This technique was utilized to prepare a novel series of 2,2′-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)bis(hydrazin-1-yl-2-ylidene)]bis[(5-arylidine)thiazol-4(5H)-one] via condensation of 2,2′-[(2,6-dimethylpyridine-3,5-diyl)bis(ethan-1-yl-1-ylidene)bis(hydrazin-1-yl-2-ylidene)]bis(thiazol-4(5H)-one) and carbonyl compounds. The structures of the newly synthesized chalcones were confirmed by FT-IR, 1H NMR, 13C NMR, and MS (ESI) data. These spectroscopic results verified the successful formation of the target bis-thiazolidinone framework. To highlight the significance of the synergistic biological potency of the target products as fundamental frameworks for the development of Alzheimer's treatments, molecular docking analyses were performed to investigate the potential binding configurations of the tested ligands. The molecular docking studies were in good agreement with the in vitro biological results, including acetylcholinesterase (AChE) and beta-amyloid (Aβ₁–₄₂) inhibition activities. In the docking analysis, compounds 5b, 5d, 5e, 5f, 5 l, and 5n demonstrated strong molecular interactions with 7AIS as the target protein. These findings highlight compounds that could be used as adjuvants in the management of AD. Additionally, in silico investigations of these newly synthesized substances were successfully conducted. The ADMET profiles of the studied compounds indicated favorable bioavailability characteristics.