Alzheimer’s disease represents a major public health challenge facing aging population worldwide. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease modifying therapies. Following the MTDLs approach, a small library of coumarin-based derivatives was designed and synthesized, as a follow-up of our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern in position 6 or 7 was modified by introducing alkyl chains of variable lengths and carrying different terminal amino functions. Compound 13, bearing the bulkiest amine, emerged as a non-neurotoxic dual AChE/BuChE inhibitor, potentially suitable for the treatment of the middle stage of the disease. Besides, the introduction of a diethylamino spacer chain, as in compounds 4 and 10, led to nanomolar hAChE inhibitors endowed with significant inhibition of Aβ42 self-aggregation, while the reference compound was completely ineffective. Compound 10 also showed a promising neuroprotective behavior, which makes it a potential candidate to be developed into a disease-modifying agent.

Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin-Based Derivatives

MONTANARI, SERENA;BARTOLINI, MANUELA;NEVIANI, PAOLO;BELLUTI, FEDERICA;GOBBI, SILVIA;PRUCCOLI, LETIZIA;TAROZZI, ANDREA;Falchi, Federico;ANDRISANO, VINCENZA;CAVALLI, ANDREA;BISI, ALESSANDRA;RAMPA, ANGELA
2016

Abstract

Alzheimer’s disease represents a major public health challenge facing aging population worldwide. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease modifying therapies. Following the MTDLs approach, a small library of coumarin-based derivatives was designed and synthesized, as a follow-up of our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern in position 6 or 7 was modified by introducing alkyl chains of variable lengths and carrying different terminal amino functions. Compound 13, bearing the bulkiest amine, emerged as a non-neurotoxic dual AChE/BuChE inhibitor, potentially suitable for the treatment of the middle stage of the disease. Besides, the introduction of a diethylamino spacer chain, as in compounds 4 and 10, led to nanomolar hAChE inhibitors endowed with significant inhibition of Aβ42 self-aggregation, while the reference compound was completely ineffective. Compound 10 also showed a promising neuroprotective behavior, which makes it a potential candidate to be developed into a disease-modifying agent.
Montanari, Serena; Bartolini, Manuela; Neviani, Paolo; Belluti, Federica; Gobbi, Silvia; Pruccoli, Letizia; Tarozzi, Andrea; Falchi, Federico; Andrisano, Vincenza; Miszta, Przemysław; Cavalli, Andrea; Filipek, Sławomir; Bisi, Alessandra; Rampa, Angela
File in questo prodotto:
File Dimensione Formato  
ChemMedChem VQR.pdf

embargo fino al 31/10/2018

Descrizione: Accepted manuscript
Tipo: Postprint
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione - Non commerciale - Non opere derivate (CCBYNCND)
Dimensione 1.85 MB
Formato Adobe PDF
1.85 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/549859
Citazioni
  • ???jsp.display-item.citation.pmc??? 7
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 21
social impact