In vitro dual-target activities and in vivo antidiabetic effect of 3-hydroxy- N -( p -hydroxy-phenethyl) phthalimide in
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Medicinal Chemistry Research (2020) 29:2077–2088 https://doi.org/10.1007/s00044-020-02628-y
ORIGINAL RESEARCH
In vitro dual-target activities and in vivo antidiabetic effect of 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide in high-fat diet and streptozotocin-induced diabetic golden hamsters Bin Xiao 1,2 Yunfeng Xiao3 Haining Ning1 Xiaoyan Han1 Wenyan Li4 Yuheng Ma5 Na Zhao1 Guanhua Du2 Yu Dong5 Jee H. Jung6 Zhanfei She1 ●
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Received: 10 June 2020 / Accepted: 1 September 2020 / Published online: 10 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide (HNHP), which showed in vitro peroxisome proliferator-activated receptor-γ (PPAR-γ) activation and in vivo anti-inflammatory effect in our previous study, was speculated to be a dual-target lead compound because similar structures exhibited α-glucosidase inhibitory activities. To investigate the dual targeting potential, molecular docking of HNHP was performed targeting on PPAR-γ and α-glucosidase, and HNHP was found to bind with dual targets in the known active sites with relatively high affinities. The in vitro α-glucosidase inhibitory evaluation showed that HNHP inhibited the enzyme (IC50 = 0.669 µM) better than acarbose (IC50 = 49.133 µM). For in vivo antidiabetic activity study, type 2 diabetes mellitus was induced by high-fat diet (20%) and streptozotocin (30 mg/kg) in golden hamsters. The diabetic hamsters were administered with different doses (1, 2, 4 mg/kg/day) of HNHP and rosiglitazone (1 mg/kg/day, positive control) for consecutive 14 days, respectively. Compared with rosiglitazone, HNHP significantly increased the insulin sensitivity, while the fasting blood glucose, glycated hemoglobin Alc, urine sugar, body weight, food/water intake, and lipid profile of media-dose (2 mg/kg/day) group golden hamsters were significantly normalized. Furthermore, pathological investigation found that the media-dose of HNHP showed the best protection on pancreatic tissue. These findings indicated that the PPAR-γ activator HNHP possessed in vitro α-glucosidase inhibitory and in vivo antidiabetic activities. Thereby, HNHP would serve as a new dual-target optimization lead. Keywords 3-hydroxy-N-(p-hydroxy-phenethyl) phthalimide Molecular docking PPAR-γ α-glucosidase Antidiabetic ●
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Introduction
These authors contributed equally: Bin Xiao, Yunfeng Xiao
Diabetes mellitus is a chronic dysfunction in the metabolism of carbohydrate and fat, and is associated with the global increasing morbidity, mortality, and economic burden (Cho et al. 2018). Type 2 diabetes mellitus (T2DM) accounts for
* Yu Dong [email protected]
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* Jee H. Jung [email protected]
Center for New Drug Safety Evaluation and Research, Inner Mongolia Medical University, Hohhot 010110, China
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* Zhanfei She [email protected]
Department of Pharmacy, Inner Mongolia People’s Hospital, Hohhot 010017, China
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Department of Pharmacy, Inner Mongolia Medical
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