Advanced search
Start date
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors

Full text
Show less -
Chierrito, Talita P. C. [1, 2] ; Pedersoli-Mantoani, Susimaire [1, 2] ; Roca, Carlos [2] ; Sebastian-Perez, Victor [2] ; Martinez-Gonzalez, Loreto [2] ; Perez, Daniel I. [2] ; Perez, Concepcion [3] ; Canales, Angeles [4] ; Javier Canada, F. [2] ; Campillo, Nuria E. [2] ; Carvalho, Ivone [1] ; Martinez, Ana [2]
Total Authors: 12
[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ave Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil
[2] CSIC, CIB, Ramiro de Maetzu 9, Madrid 28040 - Spain
[3] CSIC, Inst Quim Med, Juan de la Cierva 3, Madrid - Spain
[4] Univ Complutense Madrid, Fac Ciencias Quim, Av Complutense S-N, Madrid - Spain
Total Affiliations: 4
Document type: Journal article
Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 145, p. 431-444, FEB 10 2018.
Web of Science Citations: 7

Alzheimer's disease (AD) is the most common form of dementia worldwide with an increasing prevalence for the next years. The multifactorial nature of AD precludes the design of new drugs directed to a single target being probably one of the reasons for recent failures. Therefore, dual binding site acetyl cholinesterase (AChE) inhibitors have been revealed as cognitive enhancers and beta-amyloid modulators offering an alternative in AD therapy field. Based on the dual ligands NP61 and donepezil, the present study reports the synthesis of a series of indolylpiperidines hybrids to optimize the NP61 structure preserving the indole nucleus, but replacing the tacrine moiety of NP61 by benzyl piperidine core found in donepezil. Surprisingly, this new family of indolylpiperidines derivatives showed very potent and selective hBuChE inhibition. Further studies of NMR and molecular dynamics have showed the capacity of these hybrid molecules to change their bioactive conformation depending on the binding site, being capable to inhibit with different shapes BuChE and residually AChE. (C) 2018 Elsevier Masson SAS. All rights reserved. (AU)

FAPESP's process: 13/50788-3 - Novel and potential anti-Alzheimer's agents: from design to preclinical studies
Grantee:Ivone Carvalho
Support type: Regular Research Grants
FAPESP's process: 12/04054-5 - Synthesis of potential acetylcholinesterase inhibitor for treating Alzheimer's Disease
Grantee:Talita Perez Cantuaria Chierrito
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 12/14114-5 - Design, synthesis and evaluation of dual binding sites acetylcholinesterase inhibitors as potential anti-Alzheimer's drug candidates
Grantee:Ivone Carvalho
Support type: Regular Research Grants
FAPESP's process: 14/10414-0 - Parallel artificial membrane permeability assay for blood-brain barrier (PAMPA-BBB) of tacrine-donepezil hybrids as potential anti-Alzheimer's drugs
Grantee:Talita Perez Cantuaria Chierrito
Support type: Scholarships abroad - Research Internship - Doctorate