Heydari Zahra, Mohammadi-Khanaposhtani Maryam, Imanparast Somaye, Faramarzi Mohammad A, Mahdavi Mohammad, Ranjbar Parviz R, Larijani Bagher
School of Chemistry, College of Science, University of Tehran, Tehran, Iran.
Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
Med Chem. 2019;15(1):8-16. doi: 10.2174/1573406414666180528110104.
Pyrano[3,2-c]quinoline derivatives 6a-n were synthesized via simple two-step reactions and evaluated for their in vitro α-glucosidase inhibitory activity.
Pyrano[3,2-c]quinoline derivatives 6a-n derivatives were prepared from a two-step reaction: cycloaddition reaction between 1-naphthyl amine 1 and malonic acid 2 to obtain benzo[h]quinoline-2(1H)-one 3 and reaction of 3 with aryl aldehydes 4 and Meldrum's acid 5. The anti- α-glucosidase activity and kinetic study of the synthesized compounds were evaluated using α-glucosidase from Saccharomyces cerevisiae and p-nitrophenyl-a-D-glucopyranoside as substrate. The α-glucosidase inhibitory activity of acarbose was evaluated as positive control.
All of the synthesized compounds, except compounds 6i and 6n, showed more inhibitory activity than the standard drug acarbose and were also found to be non-cytotoxic. Among the synthesized compounds, 1-(2-bromophenyl)-1H-benzo[h]pyrano[3,2-c]quinoline-3,12(2H,11H)-dione 6e displayed the highest α-glucosidase inhibitory activity (IC50 = 63.7 ± 0.5 µM). Kinetic study of enzyme inhibition indicated that the most potent compound, 6e, is a non-competitive inhibitor of α-glucosidase with a Ki value of 72 µM. Additionally, based on the Lipinski rule of 5, the synthesized compounds were found to be potential orally active drugs.
Our results suggest that the synthesized compounds are promising candidates for treating type 2 diabetes.
通过简单的两步反应合成了吡喃并[3,2-c]喹啉衍生物6a-n，并对其体外α-葡萄糖苷酶抑制活性进行了评估。
吡喃并[3,2-c]喹啉衍生物6a-n通过两步反应制备：1-萘胺1与丙二酸2之间的环加成反应得到苯并[h]喹啉-2(1H)-酮3，以及3与芳醛4和丙二酸亚异丙酯5的反应。使用来自酿酒酵母的α-葡萄糖苷酶和对硝基苯基-α-D-吡喃葡萄糖苷作为底物，对合成化合物的抗α-葡萄糖苷酶活性和动力学进行了研究。阿卡波糖的α-葡萄糖苷酶抑制活性作为阳性对照进行评估。
除化合物6i和6n外，所有合成化合物均显示出比标准药物阿卡波糖更强的抑制活性，并且还发现它们无细胞毒性。在合成化合物中，1-(2-溴苯基)-1H-苯并[h]吡喃并[3,2-c]喹啉-3,12(2H,11H)-二酮6e表现出最高的α-葡萄糖苷酶抑制活性(IC50 = 63.7 ± 0.5 μM)。酶抑制动力学研究表明，最有效的化合物6e是α-葡萄糖苷酶的非竞争性抑制剂，Ki值为72 μM。此外，根据Lipinski的五规则，发现合成化合物是潜在的口服活性药物。
我们的结果表明，合成化合物是治疗2型糖尿病的有前途的候选药物。
