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

[ Vol. 16 , Issue. 8 ]

Author(s):

Jinyu Liu, Zuwen Zhou, Jian Liu, Jufang Yan, Li Fan, Xuemei Tang, Jie Liu, Feifei Chen and Dacheng Yang*   Pages 835 - 845 ( 11 )

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.

Affiliation:

School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, Drug Screening Center, Chengdu DiAo Pharmaceutical Group Co. Ltd, Chengdu 610041, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, School of Life Science, Southwest University, Chongqing 400715, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715

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