Novel Multipotent Amantadine-M30D Hybrids with Highly Selective Butyrylcholinesterase Inhibition and Neuroprotective Effects as Effective Anti-Alzheimer's Agents.

As a contribution to the development of new dual/multifunctional drugs, a novel therapeutical scaffold merging key structural features from memantine and M30D was designed, synthesized, and explored for its AChE/BuChE inhibitory activity and neuroprotective effects. All synthetized hybrids were not able to inhibit AChE, but most of them exhibit inhibition with high selectivity toward butyrylcholinesterase (BuChE). Notably, among the tested compounds, amantadine/M30D hybrids with six, seven, nine, and twelve methylene groups in the spacer (, , , and ) not only highlighted having the best potency and selective butyrylcholinesterase inhibition greater than 83% but also, particularly and , elicited considerable neuroprotection when evaluated in pretreatment conditions, by reducing injury effects caused by glutamate with maximum protection reached about 47.82 ± 0.81% () and 42 ± 2.20% () in comparison with memantine (37.27 ± 2.69%). Likewise, we chose as the hit compound, which in a glutamate excitotoxity coculture model prevented astroglia reactivity and neuronal death, as well as a 91% restoration of calcium levels and an increasing ATP level in both pre-/post-treatments of 61.48 ± 4.60 and 45.16 ± 10.55%, respectively. Regarding docking studies, a blockade of the NMDA channel pore by would explain its neuroprotective response. Finally, the hit compound exhibited blood-brain barrier (BBB) permeability and human plasma stability, as well as an optimal neuropharmacokinetic profile. From a therapeutic perspective, merging key pharmacophoric features from memantine and M30D provides a new medicinal scaffold with dual-/multifunctional properties and human plasma stability for the future development of potential drugs for treating AD.