Development of tacrine-based multitarget-directed ligands as dual AChE/EGFR inhibitors with neuroprotective activity

Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which current therapies primarily rely on cholinesterase inhibitors (ChEIs). Tacrine was the first and potent ChEI, which was soon withdrawn due to hepatic side effects. Meanwhile, the epidermal growth factor receptor (EGFR) inhibitor gefitinib has shown anti-AD potential. Inspired by these findings, we designed a series of hybrid molecules by conjugating the tacrine and gefitinib pharmacophores to create dual AChE/EGFR inhibitors, aiming to ameliorate cognitive impairment. After the structure-activity relationship (SAR) studies, two lead compounds (S24-1008 and S24-1017) were identified with high target affinity. These optimized compounds exhibited moderate cytotoxicity across various neuronal cell lines. Compared to traditional EGFR inhibitors, they demonstrated superior blood-brain barrier (BBB) permeability. Furthermore, they conferred significant neuroprotection against H₂O₂- and glutamate-induced neuronal damage. In vivo studies confirmed that both S24-1008 and S24-1017 effectively reversed cognitive deficits and enhanced learning and memory in mice, with no significant change in body weight observed.