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Design and Synthesis of Novel 5-Arylisoxazole-1,3,4-thiadiazole Hybrids as α-Glucosidase Inhibitors

[ Vol. 18 , Issue. 5 ]

Author(s):

Mina Saeedi, Azadeh Eslami, Seyedeh Sara Mirfazli, Mahsa Zardkanlou, Mohammad Ali Faramarzi, Mohammad Mahdavi and Tahmineh Akbarzadeh*   Pages 436 - 444 ( 9 )

Abstract:


Background: α-Glucosidase inhibitors have occupied a significant position in the treatment of type 2 diabetes. In this respect, the development of novel and efficient non-sugar-based inhibitors is in high demand.

Objective: Design and synthesis of new 5-arylisoxazole-1,3,4-thiadiazole hybrids possessing α- glucosidase inhibitory activity were developed.

Methods: Different derivatives were synthesized by the reaction of various 5-arylisoxazole-3- carboxylic acids and ethyl 2-((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate. Finally, they were evaluated for their α-glucosidase inhibitory activity.

Results: It was found that ethyl 2-((5-(5-(2-chlorophenyl)isoxazole-3-carboxamido)-1,3,4-thiadiazol- 2-yl)thio)acetate (5j) was the most potent compound (IC50 = 180.1 μM) compared with acarbose as the reference drug (IC50 = 750.0 μM). Also, the kinetic study of 5j revealed a competitive inhibition and docking study results indicated desired interactions of that compound with amino acid residues located close to the active site of α-glucosidase.

Conclusion: Good α-glucosidase inhibitory activity obtained by the title compounds introduced them as an efficient scaffold, which merits to be considered in anti-diabetic drug discovery developments.

Keywords:

5-Arylisoxazole, docking, α-glucosidase, kinetic study, 1, 3, 4-thiadiazole, synthesis.

Affiliation:

Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Department of Medicinal Chemistry, School of Pharmacy-International Campus, Iran University of Medical Sciences, Tehran, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 1417614411, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 1417614411, Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran

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