Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR

Fang, Wei‐Shuo; Sun, Deyang; Yang, Shuang; Cheng, Chen; Moschke, Katrin; Li, Tianqi; Sun, Shanshan; Lichtenthaler, Stefan F.; Huang, Jian; Wang, Yinghong

doi:10.1016/j.bioorg.2019.103253

Cited by 8 publications

(11 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although in our previous work [13] a cell permeable BACE1 inhibitor 3 was discovered with the STD-NMR, we wished in this study to probe various positions in 1 (including 3 , 4 , 3, 6, and 8 positions) for direct conjugation of 2 or through ethylene glycol linkers, to avoid the possibly misleading of imprecise STD-NMR data.…”

Section: Design Synthesis and Enzyme Inhibitory Activity Of Series mentioning

confidence: 99%

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

“…In the previous study [13], conjugates with one to four glycols units as linkers were tested, and compound with one glycol unit (i.e., in 3) was found to be the optimal. Here, we replaced glycol linkers by other polymethylene diols, trying to optimize the length of linker more carefully (Figure 3 In addition, the acetyl group reduced inhibitory activity for all pairs of compounds (4a vs. 4b, 4c vs. 4d, 4g vs. 4h), suggesting the terminal phenol group may play a role in the enzyme inhibition.…”

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

“…In the previous study [13], conjugates with one to four glycols units as linkers were tested, and compound with one glycol unit (i.e., in 3) was found to be the optimal. Here, we replaced glycol In the previous study [13], conjugates with one to four glycols units as linkers were tested, and compound with one glycol unit (i.e., in 3) was found to be the optimal. Here, we replaced glycol linkers by other polymethylene diols, trying to optimize the length of linker more carefully (Figure 3).…”

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

“…In our previous work [13], luteolin (1) and p-hydroxy-cinnamic acid (2) ( Figure 1) were found to simultaneously bind different parts of BACE1 protein by STD-NMR experiment [14]. We designed the conjugates to link two segments through proper linkage to improve the potency.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

et al. 2019

Self Cite

View full text Add to dashboard Cite

BACE1 inhibitory conjugates derived from two natural products, luteolin (1) and p-hydroxy-cinnamic acid (2), were subjected to systematic structure modifications, including various positions in luteolin segment for conjugation, different linkers (length, bond variation), as well as various substitutions in cinnamic acid segment (various substituents on benzene, and replacement of benzene by heteroaromatics and cycloalkane). Optimal conjugates such as 7c and 7k were chosen on the basis of a series of bioassay data for further investigation.

show abstract

Section: Design Synthesis and Enzyme Inhibitory Activity Of Series mentioning

confidence: 99%

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

“…In the previous study [13], conjugates with one to four glycols units as linkers were tested, and compound with one glycol unit (i.e., in 3) was found to be the optimal. Here, we replaced glycol In the previous study [13], conjugates with one to four glycols units as linkers were tested, and compound with one glycol unit (i.e., in 3) was found to be the optimal. Here, we replaced glycol linkers by other polymethylene diols, trying to optimize the length of linker more carefully (Figure 3).…”

Section: Design Synthesis and Activity Of Series ⅱ Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Daily¹,

Kang

Park

2020

BioFactors

View full text Add to dashboard Cite

Luteolin is a widely distributed flavone herbs and vegetables. It has antioxidant and anti-inflammatory activities and improves glucose metabolism by potentiating insulin sensitivity and improving β-cell function and mass.Alzheimer's disease (AD) is induced by the deposition of amyloid-beta (Aβ) in the hippocampus and the formation of neurotoxic Aβ plaques. The Aβ deposition is associated with increased formation of Aβ from amyloid precursor protein by up-regulation of β-secretase and β-site amyloid precursor proteincleaving enzyme 1 (BACE1). Furthermore, Aβ accumulation is increased by brain insulin resistance. The impairment of insulin/IGF-1 signaling mainly in the hippocampus and brain insulin resistance is connected to signals originating in the liver and gut microbiota, known as the gut microbiota-liver-brain axis. This indicates that the changes in the production of short-chain fatty acids by the gut microbiota and pro-inflammatory cytokines can alter insulin resistance in the liver and brain. Luteolin is detected in the brain tissues after passing through the blood-brain barrier, where it can directly influence neuroinflammation and brain insulin resistance and modulate Aβ deposition. Luteolin (10-70 mg/kg bw for rodents) can modulate the systemic and brain insulin resistance, and it suppresses AD development directly, and it influences Aβ deposition by activation of the gut microbiota-liver-brain axis. In this review, we evaluate the potential of luteolin to mitigate two potential causes of AD, neuroinflammatory processes, and disruption of glucose metabolism in the brain. This review suggests that luteolin intake can enhance brain insulin resistance and neuroinflammation, directly and indirectly, to protect against the development of Alzheimer's-like disease, and the gut microbiota-liver-

show abstract

Synthesis, Spectroscopic, Computational, Biological and Molecular docking studies on 3‐allyl 2,6‐diaryl piperidin‐4‐ones

Manjula

Venkateswaramoorthi²,

Dharmaraja³

et al. 2022

ChemistrySelect

View full text Add to dashboard Cite

A series of 3‐allyl‐2,6‐diarylpiperidin‐4‐one derivatives were designed and synthesized as antimicrobial agents with good yields. The target compounds were characterized by Mass, NMR, FT‐IR and FT‐Raman spectral techniques. The optimization had been performed on the title compound using the B3LYP method with 6‐311++G(d,p) basis set. The optimized bond parameter of the title molecule was calculated by DFT method. To study the intramolecular charge transfer within the molecule, the Lewis (bonding) and Non‐Lewis (anti‐bonding) structural calculation was performed. The Non‐linear optical behaviour of the title compound was measured using first order hyperpolarizability calculation. Mulliken atomic charges and thermodynamic properties were also calculated and analyzed. In vitro antibacterial and antifungal screening for all the synthesized 3‐allyl 2,6‐diaryl piperidin‐4‐ones was evaluated for two Gram‐positive bacteria (Staphylococcus aurous, Enterococcus faecalis), three Gram‐negative bacteria Pseudomonas aeruginosa, Escherichia coliand K. pneumonia) and five fungi (Candida albicans, Aspergillus niger, Aspergillus flavus, Rhizopus sp and Mucor sp). All the compounds showed good antibacterial and antifungal activities. Molecular docking study is to demonstrate that piperidine derivatives bind to Ribonucleotide reductases (RNRs) enzymes and to evaluate whether these molecules can be used as potential drugs.

show abstract

Discovery of a series of selective and cell permeable beta-secretase (BACE1) inhibitors by fragment linking with the assistance of STD-NMR

Cited by 8 publications

References 21 publications

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

Extensive Structure Modification on Luteolin-Cinnamic Acid Conjugates Leading to BACE1 Inhibitors with Optimal Pharmacological Properties

Protection against Alzheimer's disease by luteolin: Role of brain glucose regulation, anti‐inflammatory activity, and the gut microbiota‐liver‐brain axis

Synthesis, Spectroscopic, Computational, Biological and Molecular docking studies on 3‐allyl 2,6‐diaryl piperidin‐4‐ones

Contact Info

Product

Resources

About