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 Opportunities: Regular Research Grants
• Start date: November 01, 2018
• End date: January 31, 2021
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Wanda Pereira Almeida
• Grantee: Wanda Pereira Almeida
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Daniel Fábio Kawano ; Euzebio 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)

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, 2021. (18/02879-3)

SAKATA, RENATA P.; ANTONIOLLI, GIORGIO; LANCELLOTTI, MARCELO; KAWANO, DANIEL FABIO; BARBOSA, EUZEBIO GUIMARAES; ALMEIDA, WANDA P.. Synthesis and biological evaluation of 2 '-Aminochalcone: A multi-target approach to find drug candidates to treat Alzheimer's disease. BIOORGANIC CHEMISTRY, v. 103, p. 12-pg., 2020-10-01. (18/02879-3)