Rational Design of a Structural Framework with Potential Use to Develop Chemical Reagents That Target and Modulate Multiple Facets of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized by multiple, intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress. We report a novel compound (ML) prototype of a rationally designed molecule obtained by integrating structural elements for Aβ aggregation control, metal chelation, reactive oxygen species (ROS) regulation, and antioxidant activity within a single molecule. Chemical, biochemical, ion mobility mass spectrometric, and NMR studies indicate that the compound ML targets metal-free and metal-bound Aβ (metal–Aβ) species, suppresses Aβ aggregation in vitro, and diminishes toxicity induced by Aβ and metal-treated Aβ in living cells. Comparison of ML to its structural moieties (i.e., 4-(dimethylamino)phenol (DAP) and (8-aminoquinolin-2-yl)methanol (1)) for reactivity with Aβ and metal–Aβ suggests the synergy of incorporating structural components for both metal chelation and Aβ interaction. Moreover, ML is water-soluble and potentially brain permeable, as well as regulates the formation and presence of free radicals. Overall, we demonstrate that a rational structure-based design strategy can generate a small molecule that can target and modulate multiple factors, providing a new tool to uncover and address AD complexity.

HPTLC Finger-Printing and Cholinesterase Inhibitory and Metal-Chelating Capacity of Various Citrus Cultivars and Olea europaea

“…Thus, inhibition of both AChE and BChE is an important target for the development of new anti-Alzheimer drugs. Since AD is multi-faceted disease, it is also strongly associated with metal ion dyshomeostasis and oxidative stress (4). Dysregulation of some transition metals such as iron, aluminum or copper has been very important in formation of oxidative stress and cellular damage relevant to some neurodegenerative diseases including AD and Parkinson's disease (5,6).…”

Design, Synthesis and Photochemical Reactivation of Caged Prodrugs of 8-Hydroxyquinoline-Based Enzyme Inhibitors

“…[4][5][6][7][8][9][10][11][12][13] 5-Chloro-8-hydroxy-7-iodoquinoline (clioquinol, Chart 1) has been clinically used as an antifungal and antiprotozoal drug prior to the 1970's.…”

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

“…2,[6][7] The mechanism underlying the causes and progression of AD is 10 subject to enormous research efforts, and the search for new and effective therapies is 11 justified by the lack of effective treatment options. [8][9] 12 Diagnosis of AD, as opposed to other forms of dementia, requires post-mortem 13 examination of the brain to determine the severity of neuropathological hallmarks of the 14 disease; amyloid-beta (A) plaques and neurofibrillary tangles.…”