Development of benzenesulfonamide containing 1,2,3-triazole and 1,3,4-oxadiazole hybrids as cathepsin B inhibitors and DFT calculations

Abstract

A series of twenty-one novel hybrids of 1,2,3-triazole, 1,3,4-oxadiazole, and benzenesulfonamide motifs has been synthesized and evaluated for inhibitory potency against cathepsin B (EC 3.4.22), a cysteine protease lysosomal enzyme. The most potent anti-cathepsin B compounds 9d-f were docked with the cathepsin B enzyme and free energy of binding as well as interactions involved in protein-ligand complex are reported. ADMET parameters of 9d-f were calculated to check the drug-likeness behavior as orally administrative drug candidates. HOMO-LUMO energies as well as values of other global reactivity parameters were also calculated for all the twenty-one target molecules using DFT calculations. The investigated compounds have possessed excellent inhibition potential against cathepsin B enzyme with 40.50 -76.64 % inhibition at 10 8 (% inhibition = 32.46 % at 10 8 M concentrations as compared to curcumin M concentration), the reference taken. Further, the docking obtained results were found in agreement with the experimentally observed higher anti-cathepsin activity of 9e among the docked compounds. ADMET calculations proved the compounds 9d-f as safer orally administrative drug can didates. DFT results suggest that the compounds of series 9 are better electron acceptors than their respective analogues in series 10 which in turn are better electron acceptors than their respective analogues in series 11