Abusaif Moustafa S, Sh El-Sharief Ahmed M, Mohamed Yehia A, Ammar Yousry A, Ismail Mostafa A, Aboulthana Wael M, El-Gaby Mohamed S A, Ragab Ahmed
Chemistry Department, Faculty of Science (boys), Al-Azhar University, Nasr City, 11884, Cairo, Egypt.
Chemistry Department, Faculty of Science, Al-Azhar University, Assiut, 71524, Egypt.
Sci Rep. 2025 Jun 3;15(1):19409. doi: 10.1038/s41598-025-03139-9.
In this study, a novel series of 1,2,4-triazolo[4,3-a]quinoxalines containing a sulfonamide moiety was designed and synthesized through regioselective synthesis from 2 and/ 3-hydrazino-6-(pyrrolidin-1-ylsulfonyl)quinoxaline derivatives 5 and 7. The structures of two isomers were confirmed and characterized by IR,H NMR,C NMR, and elemental analysis data. The synthesized 1,2,4-triazolo[4,3-a]quinoxaline derivatives 8-13 were evaluated for their antidiabetic activities by targeting α-amylase and α-glucosidase, as well as for their anti-Alzheimer activity by targeting acetylcholinesterase (AChE) at a concentration of 100 µM. Structure-activity relationship (SAR) analysis was conducted for all analogs, emphasizing the nature of the substituent groups at position one of the triazole nucleus and the positioning of the sulfonamide moiety. For α-amylase and α-glucosidase activity, the designed compounds exhibited moderate to good activity, with inhibitory percentage values ranging from 21.85 ± 0.01% to 64.70 ± 0.02% and from 23.93 ± 0.01% to 75.36 ± 0.01%, respectively. The N-allyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-amine derivative 10a demonstrated the most significant inhibitory activity, with percentages of 64.70 ± 0.02% and 75.36 ± 0.01% against α-amylase and α-glucosidase, respectively, in comparison to acarbose (IP = 67.33 ± 0.01% and 57.79 ± 0.01%). Furthermore, the 1,2,4-triazolo[4,3-a]quinoxaline derivatives 8-13 exhibited low to moderate inhibitory percentages against the acetylcholinesterase enzyme, except for the 1-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivative 11b which demonstrated the highest inhibitory percentage of 44.78 ± 0.01%, compared to donepezil (IP = 67.27 ± 0.60%). Moreover, the promising derivative 10a demonstrated exceptional inhibitory activity, exhibiting IC values of 3.46 ± 0.06 µM and 6.89 ± 0.09 µM against α-glucosidase and α-amylase, respectively, when compared to acarbose, which has IC values of 4.27 ± 0.06 µM and 5.90 ± 0.09 µM. Finally, molecular docking simulations were performed for compound 10a within α-amylase (PDB: 2QV4) and α-glucosidase (PDB: 3W37), while compound 11b was analyzed within acetylcholinesterase (AChE) (PDB: 4EY7) to assess binding affinity and to explore the binding interactions with the active sites of the enzymes.
在本研究中，通过2和/或3-肼基-6-(吡咯烷-1-基磺酰基)喹喔啉衍生物5和7的区域选择性合成，设计并合成了一系列含磺酰胺部分的新型1,2,4-三唑并[4,3-a]喹喔啉。通过红外光谱、氢核磁共振、碳核磁共振和元素分析数据对两种异构体的结构进行了确认和表征。以100 μM的浓度，针对α-淀粉酶和α-葡萄糖苷酶评估了合成的1,2,4-三唑并[4,3-a]喹喔啉衍生物8-13的抗糖尿病活性，并针对乙酰胆碱酯酶(AChE)评估了它们的抗阿尔茨海默病活性。对所有类似物进行了构效关系(SAR)分析，重点关注三唑核1位取代基的性质和磺酰胺部分的位置。对于α-淀粉酶和α-葡萄糖苷酶活性，设计的化合物表现出中等至良好的活性，抑制率分别为21.85±0.01%至64.70±0.02%和23.93±0.01%至75.36±0.01%。与阿卡波糖(抑制率=67.33±0.01%和57.79±0.01%)相比，N-烯丙基-[1,2,4]三唑并[4,3-a]喹喔啉-1-胺衍生物10a表现出最显著的抑制活性，对α-淀粉酶和α-葡萄糖苷酶的抑制率分别为64.70±0.02%和75.36±0.01%。此外，1,2,4-三唑并[4,3-a]喹喔啉衍生物8-13对乙酰胆碱酯酶表现出低至中等的抑制率，除了1-甲基-[1,2,4]三唑并[4,3-a]喹喔啉衍生物11b表现出最高抑制率44.78±0.01%，与多奈哌齐(抑制率=67.27±0.60%)相比。此外，有前景的衍生物10a表现出优异的抑制活性，与阿卡波糖(IC值分别为4.27±0.06 μM和5.90±0.09 μM)相比，对α-葡萄糖苷酶和α-淀粉酶的IC值分别为3.46±0.06 μM和6.89±0.09 μM。最后，对化合物10a在α-淀粉酶(PDB: 2QV4)和α-葡萄糖苷酶(PDB: 3W37)中进行了分子对接模拟，同时对化合物11b在乙酰胆碱酯酶(AChE)(PDB: 4EY7)中进行了分析，以评估结合亲和力并探索与酶活性位点的结合相互作用。
Zotero 插件