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

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

  • Eur J Med Chem. 2019 Feb 1:163:394-402. doi: 10.1016/j.ejmech.2018.12.003.
Alessandra Bisi 1,  Raquel L Arribas 2,  Matteo Micucci 3,  Roberta Budriesi 3,  Alessandra Feoli 4,  Sabrina Castellano 4,  Federica Belluti 3,  Silvia Gobbi 3,  Cristobal de Los Rios 2,  Angela Rampa 5
Affiliations

Affiliations

  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: alessandra.bisi@unibo.it.
  • 2 Instituto Teofilo Hernando and Departamento de Farmacología y Terapeutica, Facultad de Medicina, Universidad Autonoma de Madrid, C/Arzobispo Morcillo, 4, 28029, Madrid, Spain.
  • 3 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy.
  • 4 Epigenetic Med Chem Lab, Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084, Fisciano, Salerno, Italy.
  • 5 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126, Bologna, Italy. Electronic address: angela.rampa@unibo.it.
PMID: 30530190 DOI: 10.1016/j.ejmech.2018.12.003
Abstract

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.

Keywords

Alzheimer's disease; Ca(2+) channels; Dual inhibitors; GSK-3β; Maleimide-based polycyclic scaffold.

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