Ragab_2024_Drug.Dev.Res_85_e22216

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against alpha-glucosidase, alpha-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against alpha-amylase and alpha-glucosidase with inhibitory percentages between 24.34 +/- 0.01%-63.09 +/- 0.02% and 28.95 +/- 0.04%-75.36 +/- 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 +/- 0.01% and 63.09 +/- 0.02% against alpha-glucosidase and alpha-amylase compared to acarbose (IP = 57.79 +/- 0.01% and 67.33 +/- 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as alpha-glucosidase and alpha-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 +/- 0.01% and 38.95 +/- 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 +/- 0.02% compared with donepezil (IP = 67.27 +/- 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.