Novel multifunctional tacrine–donepezil hybrids against Alzheimer's disease: Design synthesis and bioactivity studies

A series of tacrine–donepezil hybrids were synthesized as potential multifunctional anti‐Alzheimer's disease (AD) compounds. For this purpose, tacrine and the benzylpiperidine moiety of donepezil were fused with a hydrazone group to achieve a small library of tacrine–donepezil hybrids. In agreement with the design, all compounds showed inhibitory activity toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC50 values in the low micromolar range. Kinetic studies on the most potent cholinesterase (ChE) inhibitors within the series showed a mixed‐type inhibition mechanism on both enzymes. Also, the docking studies indicated that the compounds inhibit ChEs by dual binding site (DBS) interactions. Notably, tacrine–donepezil hybrids also exhibited significant neuroprotection against H2O2‐induced cell death in a differentiated human neuroblastoma (SH‐SY5Y) cell line at concentrations close to their IC50 values on ChEs and showed high to medium blood–brain barrier (BBB) permeability on human cerebral microvascular endothelial cells (HBEC‐5i). Besides, the compounds do not cause remarkable toxicity in a human hepatocellular carcinoma cell line (HepG2) and SH‐SY5Y cells. Additionally, the compounds were predicted to also have good bioavailability. Among the tested compounds, H4, H16, H17, and H24 stand out with their biological profile. Taken together, the proposed novel tacrine–donepezil scaffold represents a promising starting point for the development of novel anti‐ChE multifunctional agents against AD. Novel tacrine–donepezil hybrids were designed and synthesized. The compounds exhibited cholinesterase (ChE) inhibitory activity at the low micromolar level, neuroprotective effect on SH‐SY5Y cells, and noncytotoxicity on HepG2 cells, at similar concentrations to their ChE inhibitory activity. Compounds H4, H16, H17, and H24 stand out for their promising biological profile.