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Design, synthesis and evaluation of the effect of chalcones and acyl-hydrazones derivatives on Alzheimer's Disease biochemical targets: in silico study of the pharmacokinetic properties and in vitro toxicity

Grant number: 18/02879-3
Support type:Regular Research Grants
Duration: November 01, 2018 - January 31, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Wanda Pereira Almeida
Grantee:Wanda Pereira Almeida
Home Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Daniel Fábio Kawano ; Euzébio Guimarães Barbosa ; Marcelo Lancellotti

Abstract

Alzheimer's Disease (AD) is multifactorial and requires the investigation of potential drug candidates to act on different neuropathological targets. Among these, the cholinergic deficit, the beta-amyloid peptide (A²), excitotoxicity, neuroinflammation and neurofibrillary tangles are the most relevant. A² peptide is formed by the abnormal processing of amyloid protein precursor (APP) by g and ²-secretase (BACE-1). It has been demonstrated that A² peptide, mainly that contains forty-two amino acid residues, plays a central role in AD, because it is related to the other pathological events, such as: formation of oligomers and fibrils, that injure the synapses in the brain; activation of microglia and astrocytes triggering a neuroinflammatory process; formation of neurotoxic complexes with acetylcholinesterase (AChE), through its peripheral anionic site (PAS); interaction with copper and zinc ions, leading to the oligomers stabilization, in addition to the generation of reactive oxygen species (ROS); A² promotes calcium dyshomeostase and excitotoxicity; it also alters kinases (GSK-3²) and phosphatases leading to the formation of intracellular neurofibrillary tangles. The above-mentioned importance of A² encouraged us to study the effect of some acyl-hydrazone and chalcone derivatives on several biomarkers of AD. Based on promising results, we propose in this project the synthesis and evaluation of novel acyl-hydrazones and chalcones, against A² aggregation, AChE and BACE-1 activity. In silico studies of the pharmacokinetic profile and in vitro cytotoxicity will be also conducted. (AU)

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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)
ANTONIOLLI, GIORGIO; ALMEIDA, WANDA P.; FRIAS, CAMILA C.; DE OLIVEIRA, TIAGO B.. Chalcones Acting as Inhibitors of Cholinesterases, beta-Secretase and beta-Amyloid Aggregation and other Targets for Alzheimer's Disease: A Critical Review. Current Medicinal Chemistry, v. 28, n. 21, p. 4259-4282, . (18/02879-3)

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