Synthesis of novel benzohydrazone-oxadiazole hybrids as β-glucuronidase inhibitors and molecular modeling studies

A series of compounds consisting of 25 novel oxadiazole-benzohydrazone hybrids (6-30) were synthesized through a five-step reaction sequence and evaluated for their beta-glucuronidase inhibitory potential. The IC50 values of compounds 6-30 were found to be in the range of 7.14-44.16 mu M. Compounds 6, 7, 8, 9, 11, 13, 18, and 25 were found to be more potent than D-saccharic acid 1,4-lactone (48.4 +/- 1.25 mu M). These compounds were further subjected for molecular docking studies to confirm the binding mode towards human beta-D-glucuronidase active site. Docking study for compound 13 (IC50 = 7.14 +/- 0.30 mu M) revealed that it adopts a binding mode that fits within the entire pocket of the binding site of beta-D-glucuronidase. Compound 13 has the maximum number of hydrogens bonded to the residues of the active site as compared to the other compounds, that is, the ortho-hydroxyl group forms hydrogen bond with carboxyl side chain of Asp207 (2.1 angstrom) and with hydroxyl group of Tyr508 (2.6 angstrom). The other hydroxyl group forms hydrogen bond with His385 side chain (2.8 angstrom), side chain carboxyl oxygen of Glu540 (2.2 angstrom) and Asn450 side-chain's carboxamide NH (2.1 angstrom). (C) 2015 Elsevier Ltd. All rights reserved.