Discovery of novel neuroprotective cinnamoyl-M30D hybrids targeting Alzheimer’s disease

M30D is a new multifunctional compound against AD and joined to FDA-approved drugs exhibits neuroprotective properties; and in parallel, several derivatives of cinnamic acid, are reported to benefit the treatment of AD. Novel hybrids based on the known multipotent M30D and the cinnamoyl subunit were designed, synthetized, characterized, and tested as potential anti-Alzheimer agents. The synthesized conjugates were evaluated for their neuroprotector activity using the glutamate-mediated excitotoxicity assay in neurons and astrocytes in vitro, cytotoxicity LDH release, viability luminescent ATP assay and calcium imaging. Of those, 7d (3-methoxy-4-hydroxy substituted) and 7g (3,5-dimethoxy-4-hydroxy substituted) exhibit a valuable neuroprotective response by reducing injury effects caused after glutamate exposure and/or pre-treatment, with a maximum protection reached about 45.27 ± 2.03 ( 7d ) and 40.01 ± 2.97% ( 7g ) in comparison with memantine (37.27 ± 2.69%). Likewise, we chose 7d as hit compound, which in a glutamate excitotoxity co-culture model prevented astroglia reactivity and neuronal death, as well an 88% restoration of calcium levels and an increasing ATP level in both pre/post-treatments in 53.18 ± 4.07 and 66.99 ± 6.47%, respectively. Both, computational studies and experimental data suggest that a blockade of NMDA channel pore by 7d could explain its neuroprotective effect. Finally, hit-compound 7d exhibited an optimal in silico neuropharmacokinetic profile. A new scaffold was devised by combination of the cinnamoyl moiety and the prototype M30D with a valuable neuroprotector response that should be considered in future investigations oriented at developing new drugs for treating AD.