This work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8-aminomethyl-7-hydroxy-4-methyl coumarins as potential multitarget leads for AD. The results of a computer-assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino-capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N-benzylpiperidine fragment, displayed sub-micromolar affinity for AChE, affinity for BChE, and precluded Abamyloid aggregation with a potency similar to that of 9,10-anthraquinone, making it a multitarget lead viable for further improvement.

8-Aminomethyl-7-hydroxy-4-methylcoumarins as Multitarget Leads for Alzheimer's Disease

Catto M.;Pisani L.;Carotti A.;
2016-01-01

Abstract

This work is part of our ongoing research in the discovery of multitarget therapeutic agents for Alzheimer's disease (AD). A literature screening, based on our recently proposed pharmacophore, led to the identification of 8-aminomethyl-7-hydroxy-4-methyl coumarins as potential multitarget leads for AD. The results of a computer-assisted protocol developed by us to validate multitarget hits for AD indicated that our coumarin candidates were viable leads only for AChE inhibition as later validated by biological assays. The results of BChE binding and propidium displacement assays indicate that our first generation compounds bind to the PAS site in AChE. We designed new generations of coumarin derivatives with a longer substituent at position 8 aimed at leads with more efficient interaction at the catalytic anionic site (CAS). Inhibition data and docking simulations indicated that an anilino-capping group reached the CAS region of AChE and determined also a higher inhibitory potency towards BChE. The best compound obtained, with a N-benzylpiperidine fragment, displayed sub-micromolar affinity for AChE, affinity for BChE, and precluded Abamyloid aggregation with a potency similar to that of 9,10-anthraquinone, making it a multitarget lead viable for further improvement.
File in questo prodotto:
File Dimensione Formato  
2016 ChemSel Dominguez.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 744.27 kB
Formato Adobe PDF
744.27 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

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/11586/248063
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 6
social impact