Discovery and optimization of novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides as bifunctional antidiabetic agents stimulating both insulin secretion and glucose uptake

Jo, Jeyun; Lee, Dahae; Park, Yeong Hye; Choi, Hong-Seok; Han, Jin‐Hee; Park, Do Hwi; Choi, You Kyung; Kwak, Jinsook; Yang, Min; Yoo, Jung‐Woo; Moon, Hyung Ryong; Geum, Dongho; Kang, Ki Sung; Yun, Hwayoung

doi:10.1016/j.ejmech.2021.113325

Cited by 15 publications

(4 citation statements)

References 39 publications

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“…Differentiation of C2C12 cells into myotubes was performed in DMEM containing 1% P/S and 2% horse serum as previously described [39]. After 4 days, treatment was performed in DMEM containing 1% P/S, 2% horse serum, 10% FBS, and 2% bovine serum albumin in the absence or presence of schisandrin C for 16 h. Glucose uptake activity was examined by 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) uptake assay kit (Sigma-Aldrich) as described in the manufacture's protocol.…”

Section: Glucose Uptake Assaymentioning

confidence: 99%

Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells and Glucose Uptake in Skeletal Muscle Cells

Lee

Kim

et al. 2021

Molecules

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The aim of our study was to investigate the effect of three lignans (schisandrol A, schisandrol B, and schisandrin C) on insulin secretion in rat INS-1 pancreatic β-cells and glucose uptake in mouse C2C12 skeletal muscle cells. Schisandrol A and schisandrin C enhanced insulin secretion in response to high glucose levels with no toxic effects on INS-1 cells. The effect of schisandrin C was superior to that of gliclazide (positive control), a drug commonly used to treat type 2 diabetes (T2D). In addition, western blot analysis showed that the expression of associated proteins, including peroxisome proliferator-activated receptor γ (PPARγ), pancreatic and duodenal homeobox 1 (PDX-1), phosphatidylinositol 3-kinase (PI3K), Akt, and insulin receptor substrate-2 (IRS-2), was increased in INS-1 cells after treatment with schisandrin C. In addition, insulin secretion effect of schisandrin C were enhanced by the Bay K 8644 (L-type Ca2+ channel agonist) and glibenclamide (K+ channel blocker), were abolished by the nifedipine (L-type Ca2+ channel blocker) and diazoxide (K+ channel activator). Moreover, schisandrin C enhanced glucose uptake with no toxic effects on C2C12 cells. Western blot analysis showed that the expression of associated proteins, including insulin receptor substrate-1 (IRS-1), AMP-activated protein kinase (AMPK), PI3K, Akt, glucose transporter type 4 (GLUT-4), was increased in C2C12 cells after treatment with schisandrin C. Schisandrin C may improve hyperglycemia by enhancing insulin secretion in pancreatic β-cells and improving glucose uptake into skeletal muscle cells. Our findings may provide evidence that schisandrin C may be beneficial in devising novel anti-T2D strategies.

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Section: Glucose Uptake Assaymentioning

confidence: 99%

Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells and Glucose Uptake in Skeletal Muscle Cells

Lee

Kim

et al. 2021

Molecules

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“…According to the World Health Organization’s data, T2DM continues to be the most common and fastest rising health problem in developing countries [ 54 ]. In T2DM, long-term high glucose levels trigger the deterioration of cellular functions, especially inflammatory and oxidative stress, leading to the development of serious chronic diabetic complications such as neuropathy, cataracts, and atherosclerosis [ 55 ]. One of the therapeutic approaches to reducing hyperglycemia is inhibition of α-glycosidase and α-amylase, which break down α-1,4 glycosidic bonds from the non-reducing ends of oligosaccharides and polysaccharides, allowing them to be absorbed by the small intestine and enter the bloodstream [ 56 ].…”

Section: Introductionmentioning

confidence: 99%

Screening of Antiglaucoma, Antidiabetic, Anti-Alzheimer, and Antioxidant Activities of Astragalus alopecurus Pall—Analysis of Phenolics Profiles by LC-MS/MS

et al. 2023

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Astragalus species are traditionally used for diabetes, ulcers, leukemia, wounds, stomachaches, sore throats, abdominal pain, and toothaches. Although the preventive effects of Astragalus species against diseases are known, there is no record of the therapeutic effects of Astragalus alopecurus. In this study, we aimed to evaluate the in vitro antiglaucoma, antidiabetic, anti-Alzheimer’s disease, and antioxidant activities of the methanolic (MEAA) and water (WEAA) extracts of the aerial part of A. alopecurus. Additionally, its phenolic compound profiles were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). MEAA and WEAA were evaluated for their inhibition ability on α-glycosidase, α-amylase, acetylcholinesterase (AChE), and human carbonic anhydrase II (hCA II) enzymes. The phenolic compounds of MEAA were analyzed by LC-MS/MS. Furthermore, total phenolic and flavonoid contents were determined. In this context, the antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), N,N-dimethyl-p-phenylene diamine (DMPD), ferric reducing antioxidant power (FRAP), cupric ions (Cu2+) reducing antioxidant capacity (CUPRAC), ferric ions (Fe3+) reducing, and ferrous ions (Fe2+) chelating methods. MEAA and WEAA had IC50 values of 9.07 and 2.24 μg/mL for α-glycosidase, 693.15 and 346.58 μg/mL for α-amylase, 1.99 and 2.45 μg/mL for AChE, and 147.7 and 171.7 μg/mL for hCA II. While the total phenolic amounts in MEAA and WEAA were 16.00 and 18.50 μg gallic acid equivalent (GAE)/mg extract, the total flavonoid contents in both extracts were calculated as 66.23 and 33.115 μg quercetin equivalent (QE)/mg, respectively. MEAA and WEAA showed, respectively, variable activities on DPPH radical scavenging (IC50: 99.02 and 115.53 μg/mL), ABTS radical scavenging (IC50: 32.21 and 30.22 µg/mL), DMPD radical scavenging (IC50: 231.05 and 65.22 μg/mL), and Fe2+ chelating (IC50: 46.21 and 33.01 μg/mL). MEAA and WEAA reducing abilities were, respectively, Fe3+ reducing (λ700: 0.308 and 0.284), FRAP (λ593: 0.284 and 0.284), and CUPRAC (λ450: 0.163 and 0.137). A total of 35 phenolics were scanned, and 10 phenolic compounds were determined by LC-MS/MS analysis. LC-MS/MS revealed that MEAA mainly contained isorhamnetin, fumaric acid, and rosmarinic acid derivatives. This is the first report indicating that MEAA and WEAA have α-glycosidase, α-amylase, AChE, hCA II inhibition abilities, and antioxidant activities. These results demonstrate the potential of Astragalus species through antioxidant properties and enzyme inhibitor ability traditionally used in medicine. This work provides the foundation for further research into the establishment of novel therapeutics for diabetes, glaucoma, and Alzheimer’s disease.

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“…[4] Pyrazole and its derivatives are a very significant class of biologically active drugs in the pharmaceutical industry. These types of scaffolds are known for their various biological activities such as antibacterial, [5] antidiabetic, [6] antifungal, [7] anti-inflammatory, [8] antimalarial, [9] antimicrobial, [10] antioxidant, [11] antiproliferative, [12] antiviral, [13] cytotoxic, [14] anticancer, [15] Fungicides, [16] gastric secretion stimulatory, [17] herbicidal, [18] insecticides, [19] and kinase inhibitors [20] etc. Pyrazolone and pyrazole ring scaffolds are present in many drug molecules as a main structural motif such as Crizotinib, Celecoxib, Ruxolitinib, Aminophenazone, and Epirizole as shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Greener Synthetic Approach for 4,4′‐(Arylmethylene)bis(3‐methyl‐1H‐pyrazol‐5‐ol) Derivatives in an Aqueous Medium using Theophylline as a Catalyst

Pund,

Dhumal,

Deshmukh

et al. 2023

ChemistrySelect

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Herein, we report an efficient, convenient and environmentally benign method for the synthesis of 4,4′‐(arylmethylene)bis(3‐methyl‐1H‐pyrazol‐5‐ol) derivatives. The reaction of aromatic aldehydes with 3‐methyl‐1‐phenyl‐5‐pyrazolone or 5‐methyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one in the presence of theophylline catalyst delivered the series of bis‐pyrazole compounds in very high yields. The method has successfully demonstrated the utility of theophylline as an expedient, eco‐friendly and green catalyst in an aqueous medium.

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Discovery and optimization of novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides as bifunctional antidiabetic agents stimulating both insulin secretion and glucose uptake

Cited by 15 publications

References 39 publications

Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells and Glucose Uptake in Skeletal Muscle Cells

Schisandrin C Affects Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells and Glucose Uptake in Skeletal Muscle Cells

Screening of Antiglaucoma, Antidiabetic, Anti-Alzheimer, and Antioxidant Activities of Astragalus alopecurus Pall—Analysis of Phenolics Profiles by LC-MS/MS

Greener Synthetic Approach for 4,4′‐(Arylmethylene)bis(3‐methyl‐1H‐pyrazol‐5‐ol) Derivatives in an Aqueous Medium using Theophylline as a Catalyst

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