Synthesis, Molecular Docking and β-Glucuronidase Inhibitory Potential of Indole Base Oxadiazole Derivatives

Abstract

β-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 β-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 β-glucuronidase. Majority of the compounds showed potent inhibitory potential with IC50 values ranging between 0.9 ± 0.01 to 46.4 ± 0.9 µM, under positive control of standard drug d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 µM). Structural activity relationship (SAR) has been established for all synthesized compounds. To shed light on molecular interactions between the synthesized compounds and β-glucuronidase, 1, 4, and 6 compounds were docked into the active binding site of β-glucuronidase. The obtained results showed that this binding is thermodynamically favorable and β-glucuronidase inhibition of the selected compounds increases with the number of hydrogen bonding established in selected compound-β-glucuronidase complexes.

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

“…34). However, bioisosteric replacement attempt with oxadiazole proved that thiadiazole unit is preferred for stronger inhibition [206]. The strongest potency remained with 2,3-dihrdoxy substituted derivative 131 (IC 50 ¼ 0.90 mM), although 2-Cl derivative had an outlying potency.…”

Beta-Glucuronidase Inhibition by Constituents of Mulberry Bark

“…After that, the optimized structure of EcGUS was processed using the automatic tools in AutoDock Tools to remove the water of protein crystallization, add hydrogen atoms, and distribute Kollman charges. Considering the noncompetitive model of inhibition, we selected the grid dimensions of 60 × 68 × 66 Å 3 to include the section of the protein during docking simulations, and then it was used for docking. According to Lamarck genetic algorithm, the most favorable prediction confirmation was finally proposed.…”

“…Collectively, our findings demonstrated that the flavonoids in Mulberry bark displayed strong E. coli β-glucuronidase inhibition activity, suggesting that Mulberry bark might be a promising dietary supplement for ameliorating β-glucuronidase-mediated intestinal toxicity. diseases and drug/diet interventions via deconjugation of a variety of glucuronides into free aglycones, resulting in a relatively high local exposure of toxic compounds in the colonic mucosa [3][4][5]. One classical example is the regeneration of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN38) from the O-glucuronide of SN38 (SN38G), in which β-GUS-catalyzed SN38G hydrolysis has been validated as the leading cause of the intestinal toxicity of irinotecan [6][7][8].…”

“…One classical example is the regeneration of the active metabolite 7-ethyl-10-hydroxycamptothecin (SN38) from the O-glucuronide of SN38 (SN38G), in which β-GUS-catalyzed SN38G hydrolysis has been validated as the leading cause of the intestinal toxicity of irinotecan [6][7][8]. Previous investigations have also demonstrated that the microflora β-GUS activity in some diseases (such as colon cancer) was much higher than that in healthy persons [3,9,10]. The elevated microflora β-GUS activity increased the intestinal exposure of toxic compounds, leading to undesirable effects or severe side effects [11,12].…”

Highly sensitive light-up near-infrared fluorescent probe for detection and imaging of β-glucuronidase in human serum, living cells and tumor-bearing mice

“…β-Glucuronidase (GUS), a member of the lysosomal glycosidase family, can hydrolyze the glucuronide bond at the non-reducing termini of glycosaminoglycans, thereby leading to the degradation of proteoglycans and the destruction of extracellular matrix, which ultimately facilitates tumor invasion and metastasis [3,4]. Abnormal GUS overexpression is associated with the development of various cancers, including liver cancer [5], gastric cancer [6], colon cancer [7], and pancreatic adenocarcinoma [8]. Thus, GUS has been regarded as a tumor biomarker [9,10].…”