Design, synthesis, characterization, and enzymatic inhibitory activity of new dual triazole nucleobase analogues linked benzenesulfonamides moiety

Eighteen new dual triazole nucleobase analogues linked benzenesulfonamides moiety ( 5a-r ) were synthesized via Copper(I)-catalysed Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition reaction (click chemistry) between double propargylated uracil derivatives and substituted aryl azides. The structures of the synthesized compounds were confirmed by using spectroscopic techniques, including 1 H NMR, 13 C NMR, 2D NMR, and mass spectrometry (HRMS). These eighteen synthesized compounds were examined for their in vitro inhibitory activities against key digestive enzymes- α-amylase, lipase, cathepsin B, and pepsin, while showing a notable activation of trypsin. The outcomes revealed significant inhibition potential, with the compound 5j showing maximum inhibition against α-amylase (79.84 %), and the compound 5n showing maximum inhibition against lipase (74.92 %), while the compounds 5 m , 5b exhibit the highest pepsin (84.12 %) and cathepsin B (73.42 %) inhibition, respectively. Interestingly, the compound 5j displayed activation of trypsin up to 173.10 %. These experimental results were further supported by molecular docking analyses, which revealed strong binding interactions of the synthesized compounds with the active sites of the enzymes. Binding energy analyses confirmed the superior interactions compared to reference ligands such as curcumin, starch, orlistat, and olive oil. In general, this study emphasizes the potential of these dual triazole nucleobase analogues (5a-r) as promising enzyme inhibitors for managing disorders associated with abnormal digestive enzyme activity.