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Synthesis of potential acetylcholinesterase inhibitor for treating Alzheimer's Disease

Grant number: 12/04054-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2012
Effective date (End): March 31, 2016
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Ivone Carvalho
Grantee:Talita Perez Cantuaria Chierrito
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):14/10414-0 - Parallel artificial membrane permeability assay for blood-brain barrier (PAMPA-BBB) of tacrine-donepezil hybrids as potential anti-Alzheimer's drugs, BE.EP.DR


The Alzheimer's disease (AD) is a process that causes a progressive and irreversible decline of cognitive functions, which includes no organized behavior and psycothic symptoms. The World Health Organization takes a preview that in 20 years, the mental and neurological diseases will be the second cause of death in the world. In the point of neuropathologic view it is observed in the brain of the patients with AD, diffuse cortical atrophy, the presence of senile plaques, neurofibrillary tangles and neuronal loss. Additionally, accumulation of ²-amiloid protein in the senile plaques and the microtubuline tau in neurofibrillary tangles are also observed. Problems with the transmission of acetylcholine and acetyltransferases occur in affected patients. The progression of the disease symptoms is associated with structural changes in cholinergic synapses in certain brain regions and consequent impairment of cholinergic neurotransmission. The AD is complex and nowadays the therapeutic treatment offers only limited and few benefits for the patients, due to the complexity of the molecular disease, it is essential to search another alternative for the treatment to AD. Thus, this project previews the synthesis of the donepezil-tacrine hybrid (drugs that inhibit the acetylcholinesterase), with the potential to act in two therapeutics targets by (i) inhibition of acetylcholinesterase at both active and peripheral sites, as demonstrated by molecular modeling studies, and (ii) the peptide A² neurotoxic aggregation induced by acetylcholinesterase, in the attempt to stop the progression of the disease. The synthetic strategy involves the condensation of 5,6-dimethoxy-indanone with a 4-piperidinyl carbaldehyde, which carry an 4-azido-quinolinyl core, followed by one pot reduction of the olefinic bond formation and azide group. The hybrid will be tested in acetylcholinesterase inhibition assays using Ellman method and its ability to inhibit protein A² neurotoxic aggregation will be assessed by thioflavin T fluorescent method. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CHIERRITO, TALITA P. C.; PEDERSOLI-MANTOANI, SUSIMAIRE; ROCA, CARLOS; SEBASTIAN-PEREZ, VICTOR; MARTINEZ-GONZALEZ, LORETO; PEREZ, DANIEL I.; PEREZ, CONCEPCION; CANALES, ANGELES; JAVIER CANADA, F.; CAMPILLO, NURIA E.; CARVALHO, IVONE; MARTINEZ, ANA. Chameleon-like behavior of indolylpiperidines in complex with cholinesterases targets: Potent butyrylcholinesterase inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 145, p. 431-444, FEB 10 2018. Web of Science Citations: 5.
CHIERRITO, TALITA P. C.; PEDERSOLI-MANTOANI, SUSIMAIRE; ROCA, CARLOS; REQUENA, CARLOS; SEBASTIAN-PEREZ, VICTOR; CASTILLO, WILLIAN O.; MOREIRA, NATALIA C. S.; PEREZ, CONCEPCION; SAKAMOTO-HOJO, ELZA T.; TAKAHASHI, CATARINA S.; JIMENEZ-BARBERO, JESUS; JAVIER CANADA, F.; CAMPILLO, NURIA E.; MARTINEZ, ANA; CARVALHO, IVONE. From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer's disease. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 139, p. 773-791, OCT 20 2017. Web of Science Citations: 10.
MANTOANI, SUSIMAIRE P.; CHIERRITO, TALITA P. C.; VILELA, ADRIANA F. L.; CARDOSO, CARMEN L.; MARTINEZ, ANA; CARVALHO, IVONE. Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors. Molecules, v. 21, n. 2 FEB 2016. Web of Science Citations: 18.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
CHIERRITO, Talita Perez Cantuaria. Synthesis of potencial acetylcholinesterase inhibitor to Alzheimer disease treatment. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto Ribeirão Preto.

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