Structure-activity Relationships for Bergenin Analogues as ^|^beta;-Secretase (BACE1) Inhibitors

BACE1 (β-secretase, memapsin 2, Asp2) has emerged as a promising target for the treatment of Alzheimer's Disease. BACE1 is an aspartic protease which functions in the first step of the pathway leading to the production and deposition of amyloid-β peptide (Aβ). Its gene deletion showed only mild phenotypes. BACE1 inhibition has direct implications in the Alzheimer's Disease pathology without largely affecting viability. However, inhibiting BACE1 selectively in vivo has presented many challenges to medicinal chemists. Since its identification in 2000, inhibitors covering many different structural classes have been designed and developed. These inhibitors can be largely classified as either peptidomimetic or non-peptidic inhibitors. Progress in these fields resulted in inhibitors that contain many targeted drug-like characteristics. In this review, we describe structure-based design strategies and evolution of a wide range of BACE1 inhibitors including compounds that have been shown to reduce brain Aβ, rescue the cognitive decline in transgenic AD mice and inhibitor drug candidates that are currently in clinical trials.

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“…340 Geraniin, 179 , was isolated from geranium thunbergii. It was found to have a BACE1 IC 50 of 4.0 μM.…”

Section: Natural Products With Bace1 Inhibitory Activitymentioning

confidence: 99%

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

2014

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“…Bergenin (1) itself is a good scavenger of hydroxyl radicals but not so effective in scavenging other free radicals like superoxide radical and DPPH [33,35,41,42,50,52,55,64,110,111,148,188,189]. Significant antioxidant activity of bergenin in hydrogen peroxide, ABTS, DPPH and inhibition of lipid peroxidation assays with IC 50 values 32.54, 75.06, 165.35 and 365.12 μg/mL, respectively, was reported by Srinivasan et al [54].…”

Section: Antioxidant Activitymentioning

confidence: 95%

“…8,10-Di-O-methylbergenin (7) was synthesized by methylation of bergenin (1) and norbergenin (2) with diazomethane [97,139]. Shah et al have prepared the alkyl derivatives of bergenin (7,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50) by treating alkyl halides with bergenin (1) under mild basic conditions [107] (Fig. 3).…”

Section: Alkylationmentioning

confidence: 99%

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Diversity, pharmacology and synthesis of bergenin and its derivatives: Potential materials for therapeutic usages

Bajracharya

2015

Fitoterapia

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“…However, bergenin has a range of other actions. It is a β‐secretase antagonist and was also shown to inhibit acetyl and butyryl cholinesterases as well as reversing NMDA‐induced cell loss and cognitive deficits produced by scopolamine (Barai et al., 2019; Kashima & Miyazawa, 2013). Therefore it is not clear whether the observed effects on cognition were due to PTP1B inhibition or other mechanisms.…”

Section: Role Of Pi3k/akt and Tyrosine Phosphatases In Models Of Ad Pmentioning

confidence: 99%

Mini‐review: Role of the PI3K/Akt pathway and tyrosine phosphatases in Alzheimer's disease susceptibility

Curtis

Bandyopadhyay²

2020

Annals of Human Genetics

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A variety of findings from in vitro experiments and animal models support the hypothesis that one contribution to pathogenesis in Alzheimer's disease (AD) is enhanced phosphorylation of tau protein, which may be triggered by amyloid β (Aβ) and mediated by impaired activity of the PI3K/Akt signaling pathway. A number of tyrosine phosphatases act to reduce PI3K/Akt activity, and inhibition of tyrosine phosphatases is protective against Aβ toxicity in cell cultures and whole animals. Results from analysis of exome sequenced late onset AD cases and controls similarly show that rare coding variants predicted to damage PI3K functioning increase AD risk, whereas those which are predicted to damage genes for tyrosine phosphatase genes are protective. Taken together, these results support the proposition that tyrosine phosphatase antagonists might be trialed as therapeutic agents to protect against the development of AD.

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Structure-activity Relationships for Bergenin Analogues as ^|^beta;-Secretase (BACE1) Inhibitors

Cited by 11 publications

References 46 publications

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease

Diversity, pharmacology and synthesis of bergenin and its derivatives: Potential materials for therapeutic usages

Mini‐review: Role of the PI3K/Akt pathway and tyrosine phosphatases in Alzheimer's disease susceptibility

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