Abstract
There is an urgent need to propose effective treatments for Alzheimer’s disease (AD). Although the origin of the disease is poorly understood, several therapeutic options have been proposed. The new therapeutic approaches targeting biometal-mediated neurodegenerative pathways appear to be interesting ones. As a continuation of our preceding studies, two novel series of advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) inhibitors have been developed as multifunctional scavengers. This extended work allowed us to highlight the new hydroxypyridinone-diamine hybrid IIa-3 bearing a C4 alkyl linker between the two pharmacophores. This derivative exhibited preserved potent capacities to trap reactive carbonyl species (vicinal diamine function) as well as reactive oxygen species and transition metals (hydroxypyridinone moiety) in comparison with previously described lead compound 1. In addition, its good predicted absorption, distribution, metabolism and excretion (ADME) properties were correlated with a better efficacy to inhibit in vitro methylglyoxal-induced apoptosis in neuronal-like PC12 cells. This new promising agent revealed improved druglikeness and ability to prevent biometal-mediated oxidative and carbonyl stress amplification involved in AD pathogenesis.
Highlights
The development of drugs that can either alleviate or suppress Alzheimer’s disease (AD) onset and progression continues to be an urgent healthcare challenge due to the social and economic impacts of this pathology
advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) accumulation from amyloid β (Aβ) and tau proteins was reported to take part in the biometal-mediated vicious downward redox spiral involved in AD pathogenesis [3,7]
With this AD-triggering biometal dyshomeostasis hypothesis in mind, we have previously reported the development of efficient AGE/ALE inhibitors as “multitarget-directed ligands” (MTDLs) [8,9]
Summary
The development of drugs that can either alleviate or suppress Alzheimer’s disease (AD) onset and progression continues to be an urgent healthcare challenge due to the social and economic impacts of this pathology. A-Oxoaldehydes like methylglyoxal (MGO) are produced through Maillard reaction between glucose and nucleophilic amine functions of proteins or other oxidative degradations of glycolysis intermediates The condensation of these RCS (reactive carbonyl species) with proteins leads to an accumulation of deleterious advanced glycation endproducts (AGE). In AD, 4-HNE-associated modifications of proteins that are implicated in neuronal communication, neurite outgrowth, antioxidant and energetic metabolism induce extensive ferroptotic cell death [1,2] With this AD-triggering biometal dyshomeostasis hypothesis in mind, we have previously reported the development of efficient AGE/ALE inhibitors as “multitarget-directed ligands” (MTDLs) [8,9]. These hydroxypyridinone-diamine hydrid molecules appear to be able to trap RCS (vicinal diamine function) as well as ROS and transition metals (hydroxypyridinone moiety) simultaneously.
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