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

Author(s):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]

Affiliation

^[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

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 145, p. 431-444, FEB 10 2018.
• Web of Science Citations: 8

Abstract

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: 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 Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/50788-3 - Novel and potential anti-Alzheimer's agents: from design to preclinical studies
• Grantee: Ivone Carvalho
• Support Opportunities: Regular Research Grants
• 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 Opportunities: 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 Opportunities: Scholarships in Brazil - Doctorate