Multifunctional tacrine–trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties

•A series of tacrine–trolox hybrids were designed and synthesized.•All compounds showed nanomolar inhibitory activity for ChEs.•All compounds exhibited antioxidant activity close to trolox.•6d showed neuro- and hepatoprotective effects and could cross the BBB.

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Graphical abstractA series of novel tacrine–trolox hybrids were designed and synthesized as multifunctional agents for the treatment of AD. 6d was found to be the most promising compound in this series.Figure optionsDownload full-size imageDownload as PowerPoint slide