Abusaif_2025_Sci.Rep_15_19409

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,(1)H NMR,(13)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 alpha-amylase and alpha-glucosidase, as well as for their anti-Alzheimer activity by targeting acetylcholinesterase (AChE) at a concentration of 100 microM. 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 alpha-amylase and alpha-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 alpha-amylase and alpha-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(50) values of 3.46 +/- 0.06 microM and 6.89 +/- 0.09 microM against alpha-glucosidase and alpha-amylase, respectively, when compared to acarbose, which has IC(50) values of 4.27 +/- 0.06 microM and 5.90 +/- 0.09 microM. Finally, molecular docking simulations were performed for compound 10a within alpha-amylase (PDB: 2QV4) and alpha-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.