Indole bearing thiadiazole analogs: synthesis, β-glucuronidase inhibition and molecular docking study

Abstract

Background Indole based thiadiazole derivatives ( 1 – 22 ) have synthesized, characterized by NMR and HREI-MS and evaluated for β-Glucuronidase inhibition. All compounds showed outstanding β-glucuronidase activity with IC 50 values ranging between 0.5 ± 0.08 to 38.9 ± 0.8 µM when compared with standard d -saccharic acid 1,4 lactone (IC 50 value of 48.1 ± 1.2 µM). The compound 6 , a 2,3-dihydroxy analog was found the most potent among the series with IC 50 value 0.5 ± 0.08 µM. Structure activity relationship has been established for all compounds. To confirm the binding interactions of these newly synthesized compounds, molecular docking study have been carried out which reveal that these compounds established stronger hydrogen bonding networks with active site residues. Electronic supplementary material The online version of this article (10.1186/s13065-019-0522-x) contains supplementary material, which is available to authorized users.

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

“…Compounds 128 (IC 50 ¼ 2.40 mM) and 129 (IC 50 ¼ 2.50 mM) were also 3-fold and 43fold stronger respectively than their corresponding oxadiazole variants. Moreover, substitution at ortho and para-positions gave stronger inhibitors compared to meta-position, while potency in monosubstituted analogues followed the order; F ˃ OH ˃ Cl Based on the pharmacological significance of thiadiazole pharmacophore and the promising inhibitory activity of indole hybrid compound 127, hybrids of indole-thiadiazole were assembled as new class of bGLU inhibitors [205]. Generally, thiadiazole nucleus infused stronger inhibitory potencies on the resulting hybrids compared to hydrazone unit.…”

Functionalization of 2-Mercapto-5-methyl-1,3,4-thiadiazole: 2-(ω-Haloalkylthio) Thiadiazoles vs. Symmetrical Bis-Thiadiazoles

“…Several synthetic protocols for the preparation of 1,3,4-thiadiazole-containing bioactive compounds have been developed and summarised [2,8,17,[27][28][29][30][31][32][33], the main part based on ring-closure reactions. Variable procedures are applied, like intramolecular cyclization of thiosemicarbazides [15,25] or potassium salt of hydrazinodithio formate [34] in concentrated sulphuric acid, condensation of thiosemicarbazide with carboxylic acids [35], benzoic acids [36,37], or N-arylsulfonylated amino acids [38], thiocarbohydrazides with aldehydes [39], hydrazinecarbodithioates or thiosemicarbazones with hydrazonoyl chlorides [40], sulfonamide diazonium chlorides with phenacyl thiocyanate [41], etc. At the same time, methods using an already built 1,3,4-thiadiazole unit are also exploited.…”

Inhibition Properties of Arylsulfatase and β-Glucuronidase by Hydrogen Peroxide, Hypochlorite, and Peracetic Acid

“…Normally, only about 2–3% of natural estrogens are free estrogens in human, whereas the rest are in sulfate or glucuronide form. , The free natural estrogens play important roles in stimulating growth, blood flow, water retention in sexual organs, neuro- and vasoprotection, and reduction of bone loss, whereas the conjugated estrogens act as reservoirs. , Natural free estrogens in humans are accurately regulated, and once the equilibrium is disrupted, it may trigger a severe outcome. For example, humans with a significantly higher urinary arylsulfatase/β-glucuronidase activity have higher free estrogens in their body, which have been thought to be the main reason for the development of many cancers, including breast cancer, stomach cancer, ovarian cancer, colonic cancer, and so forth. − Therefore, the inhibition of arylsulfatase/β-glucuronidase has been explored as one of the effective strategies for such cancer treatment, among which STX64 has been applied in clinical trials. , …”