Alasmary Fatmah A S, Alnahdi Fatima S, Ben Bacha Abir, El-Araby Amr M, Moubayed Nadine, Alafeefy Ahmed M, El-Araby Moustafa E
a Chemistry Department, College of Science , King Saud University , Riyadh , Saudi Arabia.
b Biochemistry Department, College of Science , King Saud University , Riyadh , Saudi Arabia.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1143-1151. doi: 10.1080/14756366.2017.1363743.
Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC = 9.99 ± 0.18 µM); which is comparable to quercetin (IC = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.
血糖升高和分泌型磷脂酶A2（sPLA2）活性增加与冠心病密切相关。在本报告中，我们的目标是开发抑制sPLA2的小杂环化合物。还对标题化合物进行了α-葡萄糖苷酶和α-淀粉酶测试。选择这一系列酶是因为它们与血糖调节和糖尿病心血管并发症有关。因此，合成了两个不同系列的喹喔啉酮衍生物；3- [N' -（取代苄叉基）-肼基]-1H-喹喔啉-2-酮3a-f和1-（取代苯基）-5H- [1,2,4]三唑并[4,3-a]喹喔啉-4-酮4a-f。四种化合物显示出有前景的酶抑制作用，化合物3f和4b-d强烈抑制所有研究的促炎sPLA2的催化活性。化合物3e抑制α-葡萄糖苷酶（IC = 9.99±0.18 μM）；这与槲皮素（IC = 9.93±0.66 μM）相当，槲皮素是该酶的已知抑制剂。不幸的是，所有化合物对α-淀粉酶均显示出弱活性（IC> 200 μM）。利用基于结构的分子建模工具与sPLA2-GX以及α-葡萄糖苷酶的共晶体结构相比，对构效关系进行合理化分析。本报告介绍了对在糖尿病及其并发症中相互关联的生化无关酶具有双重活性的新型化合物。
