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Design and Synthesis of Novel 5-Arylisoxazole-1,3,4-thiadiazole Hybrids as α-Glucosidase Inhibitors
Letters in Drug Design & Discovery ( IF 1 ) Pub Date : 2021-05-01 , DOI: 10.2174/1570180817999201104125018
Mina Saeedi 1 , Azadeh Eslami 2 , Seyedeh Sara Mirfazli 3 , Mahsa Zardkanlou 4 , Mohammad Ali Faramarzi 4 , Mohammad Mahdavi 5 , Tahmineh Akbarzadeh 6
Affiliation  

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.



中文翻译:

作为 α-葡萄糖苷酶抑制剂的新型 5-芳基异恶唑-1,3,4-噻二唑杂化物的设计和合成

背景:α-葡萄糖苷酶抑制剂在 2 型糖尿病的治疗中占有重要地位。在这方面,迫切需要开发新型高效的非糖基抑制剂。

目的:设计合成具有α-葡萄糖苷酶抑制活性的新型5-芳基异恶唑-1,3,4-噻二唑杂化物。

方法:通过各种5-芳基异恶唑-3-羧酸与2-((5-氨基-1,3,4-噻二唑-2-基)硫代)乙酸乙酯反应合成了不同的衍生物。最后,评估了它们的 α-葡萄糖苷酶抑制活性。

结果:发现 2-((5-(5-(2-氯苯基)isoxazole-3-carboxamido)-1,3,4-thidiazol-2-yl)thio) 乙酸乙酯 (5j) 是最有效的化合物 (IC 50 = 180.1 μM) 与作为参考药物的阿卡波糖 (IC 50 = 750.0 μM) 相比。此外,5j 的动力学研究揭示了竞争性抑制和对接研究结果表明该化合物与位于 α-葡萄糖苷酶活性位点附近的氨基酸残基之间存在所需的相互作用。

结论:标题化合物获得的良好 α-葡萄糖苷酶抑制活性使它们成为一种有效的支架,值得在抗糖尿病药物开发中考虑。

更新日期:2021-05-01
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