Unveiling new thiazole‐clubbed piperazine derivatives as multitarget anti‐AD: Design, synthesis, and in silico studies

Abstract New thiazole‐clubbed piperazine derivatives were designed, synthesized, evaluated for their inhibitory capabilities against human acetylcholinesterase and butyrylcholinesterase ( h AChE and/or h BuChE) and β‐amyloid (Aβ) aggregation, and investigated for their metal chelating potential as multitarget agents for the treatment of Alzheimer's disease. Compounds 10 , 19–21 , and 24 showed the highest h AChE inhibitory activity at submicromolar concentrations, of which compound 10 was the most potent with a half‐maximal inhibitory concentration (IC 50 ) value of 0.151 μM. Compounds 10 and 20 showed the best h BuChE inhibitory activities (IC 50 values of 0.135 and 0.103 μM, respectively), in addition to remarkable Aβ 1–42 aggregation inhibitory activities and metal chelating capabilities. Both compounds were further evaluated against human neuroblastoma SH‐SY5Y and PC12 neuronal cells, where they proved noncytotoxic at their active concentrations against h AChE or h BuChE. They also offered a significant neuroprotective effect against Aβ 25–35 ‐induced cytotoxicity in human neuroblastoma SH‐SY5Y cells. Compound 10 displayed acceptable physicochemical properties and could pass the blood–brain barrier. The molecular docking study revealed the good binding interactions of compound 10 with the key amino acids of both the catalytic active site and the peripheral anionic site of h AChE, explaining its significant potency.