Inhibitory mechanism of O-methylated quercetins, highly potent β-secretase inhibitors isolated from Caragana balchaschensis (Kom.) Pojark

Zhumanova, Kamila; Lee, Gihwan; Baiseitova, Aizhamal; Shah, Abdul Bari; Kim, Jeong-Ho; Lee, Keun Woo; Park, Ki Hun

doi:10.1016/j.jep.2021.113935

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…Furthermore, compound 1 possessed three methoxy groups at δ H 3.86 (3H, s), 3.87 (3H, s) and 3.98 (3H, s), which were assigned to positions C‐3, C‐7 and C‐4′, respectively, based on their HMBCs. Compound 1 was identified as ayanin ( Figure 1), with the data consistent with literature values [30,31] …”

Section: Resultssupporting

confidence: 84%

“…Compound 1 was identified as ayanin (Figure 1), with the data consistent with literature values. [30,31] Compound 2, a colorless solid, was assigned a molecular formula C A para-substituted ring B, evident by δ H 7.40 (2H, d, J = 8.5, H-2', 6') and δ H 6.91 (2H, d, J = 8.5, H-3', 5') showed the presence of an AA'BB' spin system. The singlet at δ H 7.86 was characteristic of H-2 of an isoflavone, and δ H 6.52 was attributed to H-8 based on the HMBC.…”

Section: Introductionmentioning

confidence: 99%

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Antifungal Compounds from the Leaves of Rhynchosia minima

Adewole

Famuyide

McGaw

et al. 2022

Chemistry & Biodiversity

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Rhynchosia minima, commonly known as jumby bean, is used as a remedy for respiratory ailments in various parts of the world. It is also used by South African traditional healers to treat heart or chest pain. This study aimed to investigate the bioactive constituents of the leaf extracts of R. minima against selected fungal isolates that have been identified as risk factors in respiratory illness. Rhynchosia minima leaves were extracted sequentially using hexane, dichloromethane, ethyl acetate and methanol in increasing order of polarity. The extracts were subjected to repeated chromatographic techniques, for phytochemical isolation. The extracts and isolated compounds were screened against Candida albicans and Cryptococcus neoformans by determining the minimum concentration that inhibited fungal growth. Six flavonoids, one norisoprenoid and one cyclitol were isolated and characterized by 1D and 2D NMR and HR‐ESI‐MS. The extracts obtained in the study had moderate to weak antifungal activities, with MICs ranging from 312.5 to 1250.0 μg/mL against both fungi. Four isolated compounds were also screened, with two of them exhibiting activity against C. albicans (MIC=6.25 μg/mL) that was comparable to amphotericin B, the positive control. These two compounds also had better antifungal potential against C. neoformans with an MIC=6.25 μg/mL, compared to the MIC of 12.5 μg/mL of amphotericin B. Seven of the eight isolated compounds were obtained from the extracts of Rhynchosia minima for the first time. Two of the isolated compounds demonstrated activity comparable or superior to amphotericin B activity. The notable potency displayed by these compounds warrants further investigation on their development as antifungal agents.

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Section: Resultssupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Antifungal Compounds from the Leaves of Rhynchosia minima

Adewole

Famuyide

McGaw

et al. 2022

Chemistry & Biodiversity

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“…O-methylated quercetins isolated from Caragana balchaschensis (Kom.) Pojark are effective inhibitors of BACE1 revealing IC 50 values from 1.2 to 6.5 μM [ 57 ]. Nobiletin (5,6,7,8,30,40-hexamethoxyflavone), tangeretin (5,6,7,8,40-pentamethoxyflavone) and sinensetin (5,6,7,30,40-pentamethoxyflavone), the most common polymehtoxyflavones (PMFs) found in citrus peel extracts, are inhibitors of BACE1 but not other selected serine proteases [ 58 ].…”

Section: Bace1 As a Phytochemical Targetmentioning

confidence: 99%

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

O’Day

2023

Biomolecules

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An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed.

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“…This indicates that these three flavonoid compounds are relatively specific and selective toward the BACE1 enzyme. Moreover, the study by Zhumanova et al (2021) also reported that O-methylated quercetins, a flavonoid isolated from the aerial part of the endemic Caragana balchaschensis (Kom.) Pojark, were significantly effective in inhibiting BACE1 with IC 50 values ranging from 1.2 to 6.5 μM.…”

Section: Introductionmentioning

confidence: 97%

“…Hence, inhibiting BACE1 could interfere in the formation of amyloid plaque since it is the initial and rate-limiting step of Aβ production. Several inhibitors against BACE1 have been developed over the past few years ( Abeysinghe et al, 2020 ; Hampel et al, 2021 ; Zhumanova et al, 2021 ); however, most of them have failed during preclinical trials. BACE1 has a large catalytic pocket, and hence the inhibitors need to be large enough to interact with key amino acid residues of the BACE1 active site ( Coimbra et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationship Analysis of Flavonoids and Its Inhibitory Activity Against BACE1 Enzyme Toward a Better Therapy for Alzheimer’s Disease

et al. 2022

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Drug development in Alzheimer’s disease (AD) suffers from a high attrition rate. In 2021, 117 agents tested in phases I and II and 36 agents tested in phase III were discontinued. Natural product compounds may be good lead compounds for AD as they contain functional groups that are important for binding against key AD targets such as β-secretase enzyme (BACE1). Hence, in this study, 64 flavonoids collected from rigorous literature search and screening that have been tested from 2010 to 2022 against BACE1, which interferes in the formation of amyloid plaque, were analyzed. The 64 unique flavonoids can be further classified into five core fragments. The flavonoids were subjected to clustering analysis based on its structure, and each representative of the clusters was subjected to molecular docking. There were 12 clusters formed, where only 1 cluster contained compounds from two different core fragments. Several observations can be made where 1) flavanones with sugar moieties showed higher inhibitory activity compared to flavanones without sugar moieties. The number of sugar moieties and position of glycosidic linkage may also affect the inhibitory activity. 2) Non-piperazine-substituted chalcones when substituted with functional groups with decreasing electronegativity at the para position of both rings result in a decrease in inhibitory activity. Molecular docking indicates that ring A is involved in hydrogen bond, whereas ring B is involved in van der Waals interaction with BACE1. 3) Hydrogen bond is an important interaction with the catalytic sites of BACE1, which are Asp32 and Asp228. As flavonoids contain favorable structures and properties, this makes them an interesting lead compound for BACE1. However, to date, no flavonoids have made it through clinical trials. Hence, these findings may aid in the design of highly potent and specific BACE1 inhibitors, which could delay the progression of AD.

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Inhibitory mechanism of O-methylated quercetins, highly potent β-secretase inhibitors isolated from Caragana balchaschensis (Kom.) Pojark

Cited by 10 publications

References 31 publications

Antifungal Compounds from the Leaves of Rhynchosia minima

Antifungal Compounds from the Leaves of Rhynchosia minima

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

Structure–Activity Relationship Analysis of Flavonoids and Its Inhibitory Activity Against BACE1 Enzyme Toward a Better Therapy for Alzheimer’s Disease

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