Oxazole-4-carboxamide/butylated hydroxytoluene hybrids with GSK-3β inhibitory and neuroprotective activities against Alzheimer's disease

Luo, Zhiyong; Li, Shang; Zhang, Yonglei; Yin, Fucheng; Luo, Heng; Chen, Xinye; Cui, Ningjie; Wan, Siyuan; Li, Xinxin; Kong, Ling–Yi; Wang, Xiao-Bing

doi:10.1016/j.ejmech.2023.115415

Cited by 7 publications

(6 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eight compounds, 6QH, donepezil (E20), BHT, EGCG, CNS-11, BHT-6QH, BHT-E20, and BHT-CNS-11, were examined, and their structure–activity relationships are summarized in Table 1 . 6QH [ 43 ] and E20 [ 44 ] are known inhibitors of the 3β isoform of glycogen synthase kinase (GSK-3β) and acetylcholinesterase (AChE) and are associated with the hyperphosphorylation of tau and the degradation of acetylcholine in neurons, respectively. Inhibitions of GSK-3β and AChE can disrupt the tau aggregation pathway [ 45 , 46 , 47 ] and improve acetylcholine signaling [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…Note that 6QH, E20, and CNS-11 do not have antioxidant activity. To add antioxidation activity to these molecules, a BHT moiety was covalently attached to the pharmacophore regions of these molecules to create new BHT-containing hybrids, BHT–6QH [ 43 ], BHT–E20 [ 49 ], and BHT–CNS-11. The first two hybrids have demonstrated dual enzyme inhibition and antioxidant activities, while the last hybrid has potential antioxidant and tau fibril disaggregation activities that await experimental validation.…”

Section: Resultsmentioning

confidence: 99%

“…5 Tau fibril disaggregation as shown in Seidler et al [ 13 ]. 6 Antioxidation and GSK-3b inhibition as shown in Luo et al [ 43 ]. 7 Antioxidation and AChE inhibition as shown in Cai et al [ 49 ].…”

Section: Figurementioning

confidence: 93%

“…Compounds were chosen with the following properties in mind: antioxidant, anti-aggregation, and enzyme inhibition. BHT-6QH is observed to inhibit GSK-3β and has antioxidant properties [ 43 ]. BHT-E20, a hybrid of BHT and Donepezil or E20, is observed to inhibit AChE and has antioxidant properties [ 49 ].…”

Section: Methodsmentioning

confidence: 99%

“… 1 An isoform of glycogen synthase kinase 3 (GSK3) linked to tau phosphorylation in tauopathy [ 43 ]. 2 Acetylcholinesterase (AChE) linked to degraded acetylcholine (AChE) [ 44 ].…”

Section: Figurementioning

confidence: 99%

See 4 more Smart Citations

Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics

Segura,

Santos,

Flores

et al. 2024

Molecules

View full text Add to dashboard Cite

Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer’s. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer’s. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau–amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer’s drug design.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Figurementioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

“… 1 An isoform of glycogen synthase kinase 3 (GSK3) linked to tau phosphorylation in tauopathy [ 43 ]. 2 Acetylcholinesterase (AChE) linked to degraded acetylcholine (AChE) [ 44 ].…”

Section: Figurementioning

confidence: 99%

See 3 more Smart Citations