2’-Hydroxy-4’,5’-dimethyl-4-dimethylaminochalcone, a novel fluorescent flavonoid with capacity to detect aluminium in cells and modulate Alzheimer's disease targets

Abstract

Alzheimer's disease (AD) is a progressive multifactorial neurodegenerative disorder with several factors contributing to its aetiology such as abnormal protein aggregation (e.g., β-amyloid peptide), oxidative stress, alterations in neurotransmitter levels (e.g., acetylcholine, monoamines) and ion metal accumulation in the brain (e.g., aluminium), among others. Due to the complex nature of this disease, there is a critical need to develop multitarget-directed compounds to address the alternative pathways involved. In this context, the aim of this work was to synthesise a simple chalcone derivative with capacity to affect different key targets of AD neurodegeneration. Consequently, we report here a microwave-assisted synthesis of a new chalcone derivative, namely 2’-hydroxy-4’,5’-dimethyl-4-dimethylaminochalcone (1). Compound 1 selectively chelated aluminium, inhibited the aggregation of Aβ 1-42 peptide, behaved as a radical scavenger and inhibited acetylcholinesterase in vitro. An extensive spectral study (UV/visible, fluorescence and MS) of chalcone 1/Al3+ complex as well as a molecular modelling study of its 3D conformation confirmed the structure of the complex. Additionally, chalcone 1 was capable of interacting with aluminium in cell lines HEK293 T and SH-SY5Y. In conclusion, chalcone 1 is a novel probe for the detection of Al3+ in cells and, moreover, it can be regarded as a promising multifunctional ligand for AD treatment.