Synthesis and Investigation on the Antidiabetic Effect of 3-aryl-1-(5-methylisoxazol-3-ylamino)-1-(4-nitrophenyl) Propan-1-one

Author(s): Jinyu Liu , Zuwen Zhou , Jian Liu , Jufang Yan , Li Fan , Xuemei Tang , Jie Liu , Feifei Chen , Dacheng Yang* .

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 8 , 2019

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Graphical Abstract:


Background: Diabetes mellitus is the third-largest non-communicable chronic disease worldwide. There are many effective drugs, but the long-term use of these clinical drugs may cause various side effects. Therefore, it is urgent to develop new antidiabetic molecules with higher efficacy and lower toxicity.

Methods: Fifteen new 3-aryl-1-(5-methylisoxazol-3-ylamino)-1-(4-nitrophenyl)propan-1-one were synthesized directly through the Mannich reaction of 4-nitroacetophenone, 3-amino-5- methylisoxazole and aromatic aldehydes catalyzed by concentrated hydrochloric acid. The molecular structures of the products were fully characterized by 1H NMR, 13C NMR, ESI MS and HRMS. The peroxisome proliferator-activated receptor (PPAR) response element and α-glucosidase inhibitory activity of these compounds were evaluated in vitro. Molecular docking, molecular physical parameters calculation, and molecular toxicity prediction were performed to analyze the structure- activity relationship and evaluate the druggability of these compounds theoretically.

Results: All compounds exhibited weak antidiabetic activities, but compound 15 showed promising as a high performance, dual-target antidiabetic lead compound with peroxisome proliferatoractivated receptor (PPAR) response element relative agonist activity of 99.55% at 27.2 nmol·mL−1 and α-glucosidase inhibitory activity of 35.21% at 13.6 nmol·mL−1. All compounds obtained may have no cardiotoxicity, no acute toxicity, no carcinogenic, and within safe range of mutagenic risk.

Conclusion: This study identified a potential PPAR lead molecule and presented an unusual strategy for antidiabetic drug development.

Keywords: Diabetes mellitus, α-glucosidase, protein tyrosine phosphatase 1B, peroxisome proliferator-activated receptor, mannich reaction, antidiabetic drug.

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Year: 2019
Page: [835 - 845]
Pages: 11
DOI: 10.2174/1570180815666180608101529
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