Rational Design and Evaluation of Rivastigmine-Based Pleiotropic Prodrugs for the Treatment of Alzheimer’s Disease

The multifactorial origin of Alzheimer’s disease (AD) is currently being addressed with the development of combination therapy or multitarget directed ligands. If the conventional approach of targeting acetylcholinesterase (AChE) for AD treatment has limitations, it could offer opportunities for a polypharmacological approach by designing covalent pseudoirreversible prodrugs inspired by rivastigmine’s mechanism of action. This study focuses on introducing aminated drugs to the rivastigmine carbamate moiety, namely, fluoxetine and memantine, which have shown synergy with cholinesterase inhibition. These innovative carbamates target sustained drug release through covalent pseudoirreversible cholinesterase inhibition, strategically balancing inhibitory potency, selectivity, mechanism, and reactivation kinetics. This comprehensive approach demonstrates the potential of targeting ChE via a covalent mechanism and provides valuable insights into the structure–activity relationships of these derivatives. Interestingly, this study provides a useful biochemical toolbox for characterizing pseudoirreversible cholinesterase carbamate-type inhibitors. The most promising compound was evaluated in in cellulo and in vivo AD models, highlighting the potential of polypharmacological interventions as innovative and multifaceted anti-AD drugs.