Potential multitarget agents for the treatment of neurodegenerations: dual H3R/AChE inhibitors with associated chelating properties

• Grant number: 21/03387-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): December 01, 2021
• Effective date (End): May 31, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: João Paulo dos Santos Fernandes
• Grantee: Flávia Barrio Lopes
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil

Abstract

The interest in multi-target drugs, i.e., molecules capable of interacting in more than one target simultaneously, has been growing in recent years as a new way to treat complex diseases, which involve different signaling pathways, connected to each other. This is the case for neurodegenerative diseases (for example, Alzheimer's disease), which involve changes in cognition-related pathways due to reduced neurotransmission caused by neuronal death. As the processes that lead to learning and memory formation are related to the activation of cholinergic and histaminergic pathways, the modulation of targets in these pathways can represent a significant advance in the treatment of diseases that affect cognitive processes, especially allied to the antioxidant activity of chelating agents. In this regard, this project aims to synthesize and evaluate the potential of compounds such as anticholinesterase agents, histamine H3 antagonists and metal chelators, designed by overlapping structural requirements for the interaction with these selected targets. The evaluation of relative selectivity towards butyrylcholinesterase and other histamine receptors will also be carried out. The compounds will be prepared using synthetic methodologies well established in the group, which generally lead to good yields. In the end, it is expected that agents with activity on the selected targets will be identified and that they will be able to bring information about the relationships between structure and activity that allow to plan new superior compounds. (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)

LOPES, FLAVIA B.; ARANHA, CECILIA M. S. Q.; CORREA, MICHELLE F.; FERNANDES, GUSTAVO A. B.; OKAMOTO, DEBORA N.; SIMOES, LEONARDO P. M.; JUNIOR, NAILTON M. N.; FERNANDES, JOAO PAULO S.. Evaluation of the histamine H-3 receptor antagonists from LINS01 series as cholinesterases inhibitors: Enzymatic and modeling studies. CHEMICAL BIOLOGY & DRUG DESIGN, v. 100, n. 5, p. 8-pg., 2022-09-08. (21/03387-0, 19/24028-8, 16/23139-2)

ARANHA, CECILIA M. S. Q.; REINER-LINK, DAVID; LEITZBACH, LUISA R.; LOPES, FLAVIA B.; STARK, HOLGER; FERNANDES, JOAO PAULO S.. Multitargeting approaches to cognitive impairment: Synthesis of aryl-alkylpiperazines and assessment at cholinesterases, histamine H3 and dopamine D3 receptors. Bioorganic & Medicinal Chemistry, v. 78, p. 10-pg., 2022-12-19. (19/24028-8, 21/03387-0)