H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
Med Chem. 2020;16(8):1124-1135. doi: 10.2174/1573406416666200128114422.
Tyramine derivatives 3-16 were prepared and tested first time for their α- glucosidase (Sources: Saccharomyces cerevisiae) inhibitory activity by using an in vitro mechanismbased biochemical assay. All the compounds were found to be new, except compounds 3, 10-12 and 16.
In continuation of our research to synthesize and identify potent inhibitors of α-glucosidase enzyme, we intended to synthesize new inhibitors of α-glucosidase enzyme with enhanced efficacy in order to provide the basis for the better treatment of the type-II diabetic.
Tyramine (1) was allowed to react with a variety of aryl chlorides (2) to yield the corresponding amides. Synthesized compounds were then purified through normal phase column chromatography. Compounds 3-16 were then assessed for their α-glucosidase inhibitory activity in an in vitro biochemical assay. The cytotoxicity of compounds 3-16 was determined by using 3T3 mouse fibroblast cell lines.
Compounds 3-5, 8, 13, and 15-16 were found to be more active (IC50 = 103.1±0.46, 37.3±4.51, 56.7±4.2, 23.9±2.31, 43.6±2.88, 55.8±1.73, and 38.2±0.86 μM, respectively) than the acarbose, the standard inhibitor of α-glucosidase enzyme, (IC50= 840.0±1.73 μM). To determine the dissociation constants and mode of inhibition, the kinetic studies were also performed for compounds 4 and 8 (the most potent inhibitors). It was observed that compounds 4 and 8 possess noncompetitive properties as the inhibitors of α-glucosidase. All the compounds were found to be noncytotoxic, except 5 and 12 (IC50= 14.7± 0.24 and 6.6± 0.38 μM, respectively).
The current study gives the facile synthesis and identification of potent inhibitors of α- glucosidase. The new inhibitors reported here may be investigated further for the designing and development of novel anti-diabetic agents.
首次通过基于机制的体外生化测定法，对 3-16 号酪胺衍生物进行了α-葡萄糖苷酶（来源：酿酒酵母）抑制活性的测试。除化合物 3、10-12 和 16 号化合物外，所有化合物均为新化合物。
为了继续合成并鉴定α-葡萄糖苷酶的有效抑制剂，我们旨在合成新的α-葡萄糖苷酶抑制剂，以增强疗效，为更好地治疗 2 型糖尿病提供依据。
使酪胺（1）与各种芳基氯（2）反应，生成相应的酰胺。通过正相柱色谱法对合成的化合物进行纯化。然后，在体外生化测定中评估化合物 3-16 对α-葡萄糖苷酶的抑制活性。使用 3T3 小鼠成纤维细胞系测定化合物 3-16 的细胞毒性。
发现化合物 3-5、8、13 和 15-16 更为活跃（IC50=103.1±0.46、37.3±4.51、56.7±4.2、23.9±2.31、43.6±2.88、55.8±1.73 和 38.2±0.86μM），比α-葡萄糖苷酶的标准抑制剂阿卡波糖（IC50=840.0±1.73μM）更为有效。为了确定离解常数和抑制模式，还对最有效的抑制剂 4 和 8 进行了动力学研究。结果表明，化合物 4 和 8 作为α-葡萄糖苷酶的抑制剂具有非竞争性特性。除 5 和 12 号化合物（IC50=14.7±0.24 和 6.6±0.38μM）外，所有化合物均无细胞毒性。
本研究提供了简便的α-葡萄糖苷酶抑制剂的合成和鉴定方法。本文报道的新抑制剂可能会进一步研究用于设计和开发新型抗糖尿病药物。
