Minor Structural Variations of Small Molecules Tune Regulatory Activities toward Pathological Factors in Alzheimer's Disease

Abstract

Chemical tools have been valuable for establishing a better understanding of the relationships between metal ion dyshomeostasis, the abnormal aggregation and accumulation of amyloid-β (Aβ), and oxidative stress in Alzheimer’s disease (AD). Still, very little information is available to correlate the structures of chemical tools with specific reactivities used to uncover such relationships. Recently, slight structural variations to the framework of a chemical tool were found to drastically determine the tool’s reactivities toward multiple pathological facets to various extents. Herein, we report our rational design and characterization of a structural series to illustrate the extent to which the reactivities of small molecules vary toward different targets as a result of minor structural modifications. These compounds were rationally and systematically modified based on consideration of properties, including ionization potentials and metal binding, to afford their desired reactivities with metal-free or metal-bound Aβ, reactive oxygen species (ROS), and free organic radicals. Our results show that although small molecules are structurally similar, they can interact with multiple factors associated with AD pathogenesis and alleviate their reactivities to different degrees. Together, our studies demonstrate the rational structure-directed design that can be used to develop chemical tools capable of regulating individual or interrelated pathological features in AD.

New amyloid beta-disaggregating agents: synthesis, pharmacological evaluation, crystal structure and molecular docking ofN-(4-((7-chloroquinolin-4-yl)oxy)-3-ethoxybenzyl)amines

“…Furthermore, there are prediction levels for compound absorption rated as good (0), moderate (1), poor (2) and very poor (3). Most of our compounds were inside the BBB-99 and Absorption-99 ellipses, satisfying the required conditions for absorption by the intestines and the brain (Table 4).…”

“…In view of the complexity of Alzheimer's disease any molecule that hits one of these targets could be a great importance towards treating the pathological activities involved in the neurodegenerative cascade. [3][4][5][6][7] A miscellany of biochemical, pathological and genetic studies portrays the crucial functions of amyloid β in AD pathogenesis. Amyloid β plays a very important role in various factors that are conducive towards AD progression.…”

“…Molecular strategy towards quinoline hybrid (4) obtained from hybridization of reference molecules (1),(2) and(3). Synthesis of the quinoline derivatives 5a-g. Reagents and conditions: (i) NaH, dry DMF, reflux, 72 h (ii) NaBHIJOAc) 3 , anhyd.…”

Preparation of 4-Flexible Amino-2-Arylethenyl-Quinoline Derivatives as Multi-Target Agents for the Treatment of Alzheimer’s Disease

“…To further complement the ThT binding assay, A transmission electron microscopy (TEM) assay was employed to monitor and clarify the effect of compound 6b 1 on Aβ 1−42 aggregation [51,52]. As shown in Figure 6, after 24 h incubation at 37 °C, the sample of Aβ 1−42 alone had aggregated into many amyloid fibrils (Figure 6b), while a few thick fibrils were observed for the sample of Aβ 1–42 in the presence of resveratrol (Figure 6d).…”

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

“…Redox-active compounds have recently been reported as multifunctional molecules capable of targeting and regulating more than one pathological factor implicated in the pathology of AD. [25][26][27][28] This indicates the redox property as a key parameter for engineering such multifunctional small molecules; however, this concept has not been fully established. To validate this notion, a series of compact molecules (1-10; Figure 1a) were rationally designed based on the benzene scaffold considering the correlation between redox activity and reactivities against multiple pathological factors found in the AD-affected brain (i.e., free radicals, metal-free Ab, and metal−Ab; Figure 1b).…”