喹喔啉是苯并吡嗪衍生物，在制药工业中具有显着的治疗作用。它们被证明可用于对抗炎症、细菌、真菌、病毒感染、糖尿病和其他应用。最近，2024 年 1 月，FDA 批准了含有喹喔啉的新药物 erdafitinib 用于治疗某些癌症。尽管喹喔啉衍生物表现出多种生物活性以及分泌型磷脂酶 A2 (sPLA2) 在糖尿病相关并发症中的作用，但靶向 sPLA2 的喹喔啉抑制剂有效解决这些并发症的潜力仍有待探索。因此，我们设计了新型 sPLA2 和 α-葡萄糖苷酶靶向喹喔啉杂环抑制剂，以调节与糖尿病相关心血管并发症患者相关的餐后血糖升高。化合物5a-d和6a-d是通过喹喔啉酰肼与各种芳基磺酰氯缩合合成的。生物学筛选显示化合物6a是一种有效的sPLA2抑制剂（IC50=0.0475μM），而化合物6c最有效地抑制α-葡萄糖苷酶（IC50=0.0953μM），优于阳性对照阿卡波糖。此外，化合物 6a 是这两种酶的最佳抑制剂。分子对接揭示了药效团特征，强调了磺酰肼部分在这些化合物的结构设计中的重要性，从而促进了有效的 sPLA2 和 α-葡萄糖苷酶抑制剂的开发。总的来说，我们的研究结果有助于确定有前途的候选药物，用于开发治疗糖尿病的新型治疗药物。

Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds 5a-d and 6a-d were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound 6a as a potent sPLA2 inhibitor (IC50 = 0.0475 µM), whereas compound 6c most effectively inhibited α-glucosidase (IC50 = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound 6a was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.