Abstract
The beta-glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising beta-glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane (1-30) were synthesized and evaluated for in vitro beta-glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC50 = 0.50-46.5 mu M) than standardD-saccharic acid 1,4-lactone (IC50 = 48.4 +/- 1.25 mu M). Compounds with hydroxyl group like6(0.60 +/- 0.01 mu M),20(1.50 +/- 0.10 mu M) and25(0.50 +/- 0.01 mu M) exhibited the most potent inhibitory activity, followed by analogs with fluorine21(3.50 +/- 0.10 mu M) and chlorine23(8.20 +/- 0.20 mu M) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the beta-glucuronidase and displayed significant binding interactions with essential residues. Graphic abstract