Design, synthesis and evaluation of dual binding sites acetylcholinesterase inhibitors as potential anti-Alzheimer's drug candidates

• Grant number: 12/14114-5
• Support Opportunities: Regular Research Grants
• Duration: December 01, 2012 - May 31, 2015
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Ivone Carvalho
• Grantee: Ivone Carvalho
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Susimaire Pedersoli Mantoani
• Associated grant(s): 13/50788-3 - Novel and potential anti-Alzheimer's agents: from design to preclinical studies, AP.R

Abstract

Alzheimer´s disease (AD) is a process involving progressive and irreversible decline of cognitive functions which leads to disorganization of the behavior and psychotic symptoms. The World Health Organization estimates that in 20 years, mental illness and neurological disorders will be the second cause of death worldwide. It is observed in the brains of AD individuals: diffuse cortical atrophy, the presence of numerous senile plaques, neurofibrillary tangles, and neuronal loss. There is also an accumulation of ²-amyloid protein (Ab) in senile plaques and tau microtubule in neurofibrillary tangles. Disorders of acetylcholine transmission and acetyltransferase occur in affected individuals. The progression of symptoms is associated with structural changes in cholinergic synapses in some brain regions, which have consequently reduced cholinergic neurotransmission. Alzheimer's disease is complex and the current therapeutic approaches for the treatment of AD provides only transient and limited benefit for the patients, therefore, in response to molecular complexity of the disease, the search for alternative drugs for the treatment of AD is relevant. Thus, this proposal focuses on the design, synthesis and evaluation of tacrine-donepezil hybrids (both acetylcholinesterase inhibitors drugs), which have potential activity to interact with two distinct therapeutic targets, that is (i) inhibition of acetylcholinesterase in both active and peripheral sites, as demonstrated by previous studies molecular modeling, and (ii) the aggregation of neurotoxic Ab peptide induced by acetylcholinesterase in an attempt to interrupt the progression of the disease. The first synthetic strategy involves the condensation of 5,6-dimethoxy-indanone with 4-piperidinyl-carbaldehyde group to give 4-azido-quinoline intermediate, followed by simultaneous reduction of olefinic and azido groups. The second synthetic strategy involves the alkylation of the ±-position of 5,6-dimethoxy-indanone with (4-ethynyl)-benzyl tosylate or 6-heptin-1-ol tosylate to provide intermediates containing terminal alkyne function, which will be used for condensation with 4-azido-quinoline via copper (I) catalyzed 1,3-dipolar cycloaddition reaction, commonly known as copper (I) catalyzed alkyne azide cycloaddition (CuAAC) reaction. The hybrids will be tested in AChE inhibition assays by Ellman's method and the ability to inhibit the aggregation of the neurotoxic Ab protein will be achieved by thioflavin T fluorescence assays. Molecular modeling studies will be accomplished by using GOLD, BROOD e GROMACS computational programs to run docking simulations, bioisosteric substitution and molecular dynamics. (AU)

Scientific publications

(4)

(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.; et al. 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. (14/10414-0, 13/50788-3, 12/14114-5, 12/04054-5)

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. (13/50788-3, 13/01710-1, 12/14114-5, 12/04054-5)

DE ANDRADE, PETERSON; MANTOANI, SUSIMAIRE P.; GONCALVES NUNES, PAULO SERGIO; MAGADAN, CARLOS ROCA; PEREZ, CONCEPCION; XAVIER, DANILO JORDAO; SAKAMOTO HOJO, ELZA TIEMI; CAMPILLO, NURIA E.; MARTINEZ, ANA; CARVALHO, IVONE. Highly potent and selective aryl-1,2,3-triazolyl benzylpiperidine inhibitors toward butyrylcholinesterase in Alzheimer's disease. Bioorganic & Medicinal Chemistry, v. 27, n. 6, p. 931-943, MAR 15 2019. (12/14114-5, 14/04868-8, 13/50788-3)

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.; et al. 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. (12/14114-5, 13/50788-3, 12/04054-5)