Abstract
beta-glucuronidase is a lysosomal glycosidase enzyme which catalyzes the extracellular matrix of cancer and normal cells and the glycosaminoglycans of the cell membrane, which is important for cancer cell proliferation, invasion, and metastasis. Liver cancer, colon carcinoma, and neoplasm bladder are triggered by the increase of the level of beta-glucuronidase activity. The most valuable structures are indole and oxadiazole which has gain immense attention because of its pharmacological behavior and display many biological properties. Twenty-two (1-22) analogs of indole based oxadiazole were synthesized and screened for their inhibitory potential against beta-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 +/- 0.01 to 46.4 +/- 0.9 mu M, under positive control of standard drug D-saccharic acid 1,4 lactone (IC50 = 48.1 +/- 1.2 mu M). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and beta-glucuronidase, 1, 4, and 6 compounds were docked into the active binding site of beta-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and beta-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-beta-glucuronidase complexes.