Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

Author(s)

Mantoani, Susimaire P. ^[1] ; Chierrito, Talita P. C. ^[1] ; Vilela, Adriana F. L. ^[2] ; Cardoso, Carmen L. ^[2] ; Martinez, Ana ^[3] ; Carvalho, Ivone ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Dept Quim, Grp Cromatog Bioafinidade & Prod Nat, BR-14040901 Ribeirao Preto - Brazil

^[3] CSIC, Ctr Invest Biol, Madrid 28040 - Spain

• Document type: Journal article
• Source: Molecules; v. 21, n. 2 FEB 2016.
• Web of Science Citations: 14

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the -amyloid (A) protein, acting as a chaperone and increasing the number and neurotoxicity of A fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with A, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization. (AU)

• 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: 13/01710-1 - Enzyme ligand: new models of screening
• Grantee: Quezia Bezerra Cass
• Support Opportunities: Research Projects - Thematic 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