Parallel artificial membrane permeability assay for blood-brain barrier (PAMPA-BBB...
| Full text | |
| Author(s): |
de Andrade, Peterson
[1]
;
Mantoani, Susimaire P.
[1]
;
Goncalves Nunes, Paulo Sergio
[1]
;
Magadan, Carlos Roca
[2]
;
Perez, Concepcion
[3]
;
Xavier, Danilo Jordao
[4]
;
Sakamoto Hojo, Elza Tiemi
[5]
;
Campillo, Nuria E.
[2]
;
Martinez, Ana
[2]
;
Carvalho, Ivone
[1]
Total Authors: 10
|
| Affiliation: | [1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Ave Cafe S-N, BR-14040930 Ribeirao Preto - Brazil
[2] Ctr Invest Biol CIB CSIC, Ramiro de Maeztu 9, Madrid 28040 - Spain
[3] CSIC, IQM, Juan Cierva 3, Madrid 28006 - Spain
[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto - Brazil
[5] Univ Sao Paulo, Fac Philosophy Sci & Letters Ribeirao Preto, Dept Biol, Ave Bandeirantes 3900, BR-14040900 Ribeirao Preto - Brazil
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | Bioorganic & Medicinal Chemistry; v. 27, n. 6, p. 931-943, MAR 15 2019. |
| Web of Science Citations: | 1 |
| Abstract | |
Acetylcholinesterase (AChE) is the key enzyme targeted in Alzheimer's disease (AD) therapy, nevertheless butyrylcholinesterase (BuChE) has been drawing attention due to its role in the disease progression. Thus, we aimed to synthesize novel cholinesterases inhibitors considering structural differences in their peripheral site, exploiting a moiety replacement approach based on the potent and selective hAChE drug donepezil. Hence, two small series of N-benzylpiperidine based compounds have successfully been synthesized as novel potent and selective hBuChE inhibitors. The most promising compounds (9 and 11) were not cytotoxic and their kinetic study accounted for dual binding site mode of interaction, which is in agreement with further docking and molecular dynamics studies. Therefore, this study demonstrates how our strategy enabled the discovery of novel promising and privileged structures. Remarkably, compound 11 proved to be one of the most potent (0.17 nM) and selective ( > 58,000-fold) hBuChE inhibitor ever reported. (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: | 14/04868-8 - Design, synthesis and biological activity evaluation for discovery of novel acetylcholinesterase inhibitors in Alzheimer's Disease |
| Grantee: | Peterson de Andrade |
| Support type: | Scholarships in Brazil - Post-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 |