Computationally Driven Exploration of Novel bis-Thiadiazole Sulfonamides as Alzheimer's Enzyme Inhibitors: A DFT and Kinetic Perspective

In this research work, bis-thiadiazole based sulfonamide hybrid analogues (1–15) were synthesized by a novel synthetic approach. Structural confirmation was accomplished through ¹HNMR, ¹³CNMR, and HREI-MS techniques. Further, these analogues were examined for their biological activities against AChE and BuChE (Alzheimer disease). These compounds have a diverse range of potency against targeted enzymes with inhibitory concentration ranges for AChE (2.80 ± 0.30–21.10 ± 0.10 μM) and for BuChE (3.20 ± 0.10–22.40 ± 0.70 μM), respectively. Compounds 4, 9, and 11 emerged as the potent compounds against targeted enzymes and have inhibitory concentrations lower than donepezil (IC₅₀ = 5.50 ± 0.10 and 6.10 ± 0.20 μM) used as a reference drug. In addition, versatile computational approaches were adopted to determine interactive properties (by molecular docking), electronic distribution and stability (through DFT calculations), and drug likeness characteristics (by ADMET predictions) of the synthesized potent scaffolds. Product confirmation was confirmed by thin layer chromatography.