Synthesis, Biological Evaluation, and Computational Studies of Schiff's Base Derivatives of 4-(4-Amino-5-Mercapto-4H-1,2,4-Triazol-3-Yl)Benzenesulfonamide as Cathepsin B Inhibitors.

A library of benzenesulfonamide incorporated Schiff's base derivatives of 4-amino-5-mercapto-1,2,4-triazoles 1a-f, 2a-e, and 3a-e has been synthesized and evaluated in-vitro for their inhibition potential against cathepsin B enzyme. All the tested compounds possessed good to excellent anti-cathepsin B activity (40.62%-74.36%) at 10-7 m concentrations in comparison with the curcumin (51.20%) taken as reference. Among all, compound 3c has shown the highest activity exhibiting 74.36% inhibition followed by 3e and 3b (69.99% and 68.36% inhibition, respectively). Molecular docking was performed for the most active compound 3c and the reference compound, curcumin, to know their interactions in the active site of the target enzyme and the results obtained were in agreement with the experimental values. Additionally, DFT calculations were also performed to determine the values of electronic parameters including energies of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO), HOMO-LUMO energy gap, chemical hardness, chemical softness, chemical potential, electronegativity, and electrophilicity index.