8-Hydroxyquinolines: A Promising Pharmacophore Potentially Developed as Disease-Modifying Agents for Neurodegenerative Diseases: A Review

Abstract

8-Hydroxyquinoline (8HQ) is an attractive heterocyclic scaffold with well-known metal chelating property, broad-ranging pharmacological activities, and preferrable drug-likeness, thus, it had gained a continual attention in areas of drug development, especially, drug repurposing. Alzheimer's disease (AD) is one of globally health concern in an era of aging society and its management is considered challenging as effective disease-modifying drugs are still clinically unavailable. Loss of metal ion homeostasis is one of key factors contributing to pathogenesis and progression of AD in which its imbalance could trigger many related key factors and harmful events, especially, oxidative neuronal damages.Hence, restoration of homeostasis and distribution of brain's metal ions served to be a promising strategy for development of disease-modifying agents. In this review, essential key points relating to AD pathogenesis, roles of metal ions in AD, and pioneer 8HQ-based compounds are introduced. A series of recently reported 8HQbased neuroprotective compounds (i.e., derivatives, hybrids, conjugates, and metal complexes) focusing on compounds acting as metal chelators are reviewed. Related 8HQ-based neuroprotective compounds with other mechanisms of actions are also discussed. Additionally, summary of key contents is included to provide an 202

Promising 8-Aminoquinoline-Based Metal Complexes in the Modulation of SIRT1/3-FOXO3a Axis against Oxidative Damage-Induced Preclinical Neurons

“…Quinoline derivatives are well recognized for their metal-chelating properties; thus, they are widely used as pharmacophores in medicinal chemistry . The most promising scaffold, 8-hydroxyquinoline (8HQ), has been represented by its multiple therapeutic effects . Particularly, clioquinol (PBT1) and PBT2-based 8HQ exhibit neuroprotective effects in cognitive transgenic mice models as well as in clinical trials by acting as Cu/zinc ionophores. ,, Although these compounds facilitate metal uptake into the brain, the metal affinity remains limited when compared with that of metalloproteins. , This has led to the search for Cu-complexing compounds, which exhibit greater effectiveness in targeting and restoring metal homeostasis in the brain of patients with AD.…”

“… 8 The most promising scaffold, 8-hydroxyquinoline (8HQ), has been represented by its multiple therapeutic effects. 9 Particularly, clioquinol (PBT1) and PBT2-based 8HQ exhibit neuroprotective effects in cognitive transgenic mice models as well as in clinical trials by acting as Cu/zinc ionophores. 8 , 10 , 11 Although these compounds facilitate metal uptake into the brain, the metal affinity remains limited when compared with that of metalloproteins.…”