Polycyclic maleimide-based derivatives as first dual modulators of neuronal calcium channels and GSK-3β for Alzheimer's disease treatment

• DOI: 10.1016/j.ejmech.2018.12.003
• Publication Date: 2018-12-03T16:59:25Z
• Authors: Alessandra Bisi; Raquel L. Arribas; Matteo Micucci; Roberta Budriesi; Alessandra Feoli; Sabrina Castellano; Federica Belluti; Silvia Gobbi; Cristobal de los ...; Angela Rampa
• Keywords: Maleimide; GSK3B; Structure–activity relationship

Current healthcare has significantly increased the average life expectancy, leading to a consequently greater incidence of age-related diseases, such as Alzheimer's disease. Following a multitarget approach, in this paper a series of polycyclic maleimide-based derivatives were designed and synthesized aimed at simultaneously modulate neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), validated targets to combat Alzheimer' disease. Different structural modifications were performed on the polycyclic scaffold in order to investigate the structure-activity relationships and compound 10 emerged as a promising non-toxic lead compound, endowed with calcium modulating brain-addressed properties and significant GSK-3β inhibitory activity. Moreover, the easily affordable polycyclic core appears as a new appealing privileged structure in medicinal chemistry.