Role of copper chelating agents: between old applications and new perspectives in neuroscience

Abstract

The role of copper element has been an increasingly relevant topic in recent years in the fields of human and animal health, for both the study of new drugs and innovative food and feed supplements. This metal plays an important role in the central nervous system, where it is associated with glutamatergic signaling, and it is widely involved in inflammatory processes. Thus, diseases involving copper (II) dyshomeostasis often have neurological symptoms, as exemplified by Alzheimer's and other diseases (such as Parkinson's and Wilson's diseases). Moreover, imbalanced copper ion concentrations have also been associated with diabetes and certain types of cancer, including glioma. In this paper, we propose a comprehensive overview of recent results that show the importance of these metal ions in several pathologies, mainly Alzheimer's disease, through the lens of the development and use of copper chelators as research compounds and potential therapeutics if included in multi-target hybrid drugs. Seeing how copper homeostasis is important for the well-being of animals as well as humans, we shortly describe the state of the art regarding the effects of copper and its chelators in agriculture, livestock rearing, and aquaculture, as ingredients for the formulation of feed supplements as well as to prevent the effects of pollution on animal productions.

Figure 1

Chelating agents are fundamental for balancing copper dyshomeostasis in medicinal chemistry, agriculture, and animal science. Created with Inkscape.

Figure 2

Structure of bis-8-aminoquinoline ligands and their copper (II) complexes (Ceccom et al., 2012; Nguyen et al., 2014). Created with molsketch.

Figure 3

General structure of TDMQ ligands (Zhang et al., 2018). Created with molsketch.

Figure 4

Structure of 3 and 4, two of the most promising 1-benzylpyrrolidine-3-amine-based ligands (Więckowska et al., 2018; Wichur et al., 2020). Created with molsketch.

Figure 5

General structure of 3-benzylidene/benzylphthalide Mannich base derivatives and structure of compound (Z)-5 (Cao et al., 2021). Created with molsketch.

Figure 6

General structure of the 1-phenyl-3-hydroxy-4-pyridinone derivatives (Sheng et al., 2016). Created with molsketch.

Figure 7

Structures of hybrids PP-BIM, PZ-BIM, and TAC-BIM (Chaves et al., 2018a; Piemontese et al., 2018a). Created with molsketch.

Figure 8

Structure of hybrid PP-BIM-5 (Chaves et al., 2020). Created with molsketch.

Figure 9

Structure of donepezil-like compound SON38 (Brunetti et al., 2022a). Created with molsketch.

Figure 10

Structure of the donepezil-like compound 6 (Zhou et al., 2019). Created with molsketch.

Figure 11

Structure of the rivastigmine-like compound 7 (Sestito et al., 2019). Created with molsketch.

Figure 12

Structures of RIV-BIM hybrids 8 and 9 (Vicente-Zurdo et al., 2022, 2023). Created with molsketch.

Figure 13

Structure of the chalcone derivative 10 (Wang et al., 2021). Created with molsketch.

Figure 14

Structures of theranostic fluorescent chelators TBT and BTTA (Yang et al., 2016a, b). Created with molsketch.

Figure 15

The metal–protein attenuating compound X1INH (Cukierman et al., 2020). Created with molsketch.

Figure 16

Structure of DHC12 (Aguirre et al., 2017). Created with molsketch.

Figure 17

Structure of N,N,O-Chelating Salphen-like ligands and the corresponding Cu²⁺ complexes (Peña et al., 2021). Created with molsketch.

Figure 18

General structure of arylthiourea ligands and the corresponding Cu²⁺ complexes (Chrzanowska et al., 2021). Created with molsketch.

Figure 19

Structure of Metformin and its analog Metforminyn (Müller et al., 2018). Created with molsketch.