Novel Tacrine-Based Compounds: Bridging Cholinesterase Inhibition and NMDAR Antagonism

Alzheimer’s disease (AD) is a complex neurodegenerative disorder with an unclear etiology. Current treatments, primarily cholinesterase (ChE) inhibitors and N-methyl-D-aspartate receptor (NMDAR) antagonists, offer only symptomatic relief. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefits for the treatment of AD. In this study, we designed, synthesized, and biologically evaluated 16 novel tacrine (THA) derivatives, incorporating (hetero)aryl groups or deuterium at position 7 of the parent molecule to improve efficacy and reduce hepatotoxicity. The compounds were frist screened in silico to assess their oral bioavailability and potential to penetrate the CNS. In vitro assays were performed to evaluate ChE inhibition, blood-brain barrier (BBB) permeability, and hepatotoxicity. The metabolic stability of selected candidates was determined using human liver microsomes, where compound 5e exhibited improved stability, while derivatives 5i and 5m showed rapid metabolism. Notably, deuterium incorporation in compound 7 did enhance metabolic stability, probably due to metabolic switching. Given the involvement of NMDAR excitotoxicity in AD, the compounds were evaluated for their NMDAR antagonistic activity. Among them, compound 5m exhibited the most potent and voltage-independent inhibition at the GluN1/GluN2B subunits. Based on its promising in vitro profile, compound 5m was advanced to in vivo pharmacokinetic studies, confirming its BBB permeability and favorable CNS distribution. These findings underline the potential of THA-based multi-target-direct ligands in AD therapy, supporting further preclinical development to enhance efficacy and safety.