Access to novel potent pleiotropic prodrugs, targeting both butyrylcholinesterase and serotonin reuptake, with anti-amnesic activities in Alzheimer's disease model.

The treatment of Alzheimer's disease should undoubtedly be multifactorial and require a polypharmacological approach to be effective. Pleiotropic prodrugs can release, upon inhibition of a primary target, a drug that targets a second protein of therapeutic interest. Here, we describe the design of prodrugs that release a potent serotonin reuptake inhibitor, 7-hydroxysertraline, upon the inhibition of butyrylcholinesterase. Indeed, 7-hydroxysertraline is not only a ligand of the serotonin transporter but also possesses the structural requirements to yield carbamates, able to bind to the catalytic site of butyrylcholinesterase and undergo its carbamylation. This behavior could result in a pseudo-irreversible inhibition of butyrylcholinesterase, followed by release of the serotonin reuptake inhibitor. Several carbamates of 7-hydroxysertraline were synthesized and evaluated in vitro for their acetyl- and butyrylcholinesterase inhibitory activities and their affinity for the serotonin transporter. Structure-activity relationships were then established based on a molecular modelling study. Investigations into cholinesterase inhibition kinetics have been conducted, resulting in the selection of two prodrugs for in vivo evaluation in an Alzheimer's disease mouse model. One of these, compound 8e, provided complete protection against short- and long-term memory deficits induced by intracerebroventricular administration of β-amyloid oligomers. This makes compound 8e a promising candidate for preclinical development as a possible treatment for Alzheimer's disease.