Résumé
Alzheimer's disease (AD) remains an incurable neurodegenerative disorder, requiring novel therapeutic strategies. We developed multitarget ligands designed to inhibit human butyrylcholinesterase (hBChE) and activate the sigma-1 receptor (S1R), addressing both cholinergic dysfunction and neuroinflammation, the latter being reduced through action on both targets. The (pseudo)-irreversible carbamate 18c emerged as the most promising compound, exhibiting potent and selective hBChE inhibition (IC 50 = 3.3 nM, 45-fold selectivity over human acetylcholinesterase) and strong S1R agonistic activity (IC 50 = 25 nM, EC 50 = 99 nM) determined in a radioligand binding assay and by S1R-BiP dissociation. Its cleavage product 14c (after carbamate hydrolysis by hBChE) retained dual activity (IC 50 (hBChE) = 269 nM, IC 50 (S1R) = 20 nM, and EC 50 (S1R) = 279 nM). Both compounds reduced lipopolysaccharide (LPS)-induced pro-inflammatory activation profile in the microglial N9 cells while preserving anti-inflammatory marker expression, thereby indicating an overall immunomodulatory effect. In vivo, inhibitor 18c improved cognitive deficits in a mouse model with Aβ 25-35 -induced neurotoxicity, enhancing short-and long-term memory in Y-maze and passive avoidance tests at dosages as low as 0.1-1 mg/kg. These findings highlight the potential of dual-targeting hBChE/S1R strategies for AD therapy.