Β-glucuronidase Inhibitors Research Articles

Theoretical investigation and design of some indole derivatives as potent \u03b2-glucuronidase inhibitors

Backgroundβ-glucuronidase enzyme is mostly found in plants and animals. It plays a vital role in detoxification of reactive metabolites that are interrelated to several illnesses and the growth of colon cancer. It speeds up the breaking down of β-glucuronosyl-O-bonds. Lack of β-glucuronidase enzyme leads to Sly syndrome in humans, and overexpression of this enzyme leads to many diseases. Therefore, it becomes necessary to mediate the effect of this enzyme.ResultTheoretical investigation via QSAR modeling on 30 indole derivatives was performed to build a model which could be used to predict the activity of the indole derivatives. QSAR was carried out using multi-linear regression (MLR) method utilizing genetic function approximation (GFA) to develop the QSAR models. A very high predictive QSAR model was reported based on its statistical fitness with good internal and external validation parameters: R2trng = 0.954942, Qcv2 = 0.925462, R2test = 0.855393, and LOF = 0.042924. Molecular docking on the 30 indole derivatives was also performed to screen and identify the lead compound that would be used as template for designing new indole compounds. The docking investigation reveals that ligand 10 binds very tight in the binding pocket of β-glucuronidase enzyme with binding energy of − 9.5 kcal/mol. The ligand (10) was chosen as a template for designing new β-glucuronidase inhibitors. The four design compounds were found to be better than the template and the standard drug (D-saccharic acid 1, 4-lactone) with binding energies of − 9.6, − 9.7, − 9.8, and − 9.9 kcal/mol.ConclusionA very high predictive QSAR model with good internal and external validation parameters: R2trng = 0.954942, Qcv2 = 0.925462, R2test = 0.855393, and LOF = 0.042924, was built and reported in this study. Molecular docking investigation reveals that the most potent compound among all the data set was compound 10 with binding energy of − 9.5 kcal/mole. It bound to the binding pocket of β-glucuronidase enzyme via hydrophobic, electrostatic, and hydrogen bond, and it was retained as template for designing new indole compounds. The design compound with serial number ID 4 was identified to have the highest binding energy of − 9.9 kcal/mole among the designed compounds. It bound to the binding site of the β-glucuronidase enzyme via halogen, hydrophobic, electrostatic, and hydrogen bond. The design compounds were discovered to be better than the template used in the design and the standard drug.

Screening of Plants Hydro-Alcoholic Extracts from Kerman for their Inhibition of β-Glucuronidase Activity

In neonatal jaundice, β-glucuronidase converts conjugated bilirubin into the unconjugated form and increases its level in the blood. Many natural compounds have been identified as β-glucuronidase inhibitors. The aim of this study was to evaluate the effect of hydro-methanolic extracts of 100 plants on β-glucuronidase. The β-glucuronidase activity was measured by a spectrophotometric method using Phenolphthalein glucuronide and 4-nitrophenyl β-D-glucuronide. Kinetic study of the enzyme was performed in the presence and absence of the plant extract. It was revealed that from hydro-methanolic (70%) extracts, Rosa damascena and Ipomoea tricolor showed more than 85% inhibitory effect on β-glucuronidase. Rosa damascena showed competitive inhibition, and Ipomoea tricolor showed non-competitive inhibition. The Km and Vmax values for β-glucuronidase were 23.32 mM and 0.814 mM min-1, respectively. When using 4-nitrophenyl β-D-glucuronide, Stevia and Cerasus avium showed more than 65% inhibitory effect on β-glucuronidase. Both Stevia and Cerasus avium showed non-competitive inhibition. The Km and Vmax values for β-glucuronidase were 16.98 mM and 0.936 mM min-1, respectively. None of the plant extracts showed an activation effect on the enzyme. The data suggest that these plants might be good candidates for the treatment of neonatal jaundice and its related diseases.

β-Glucuronidase inhibitors from Malaysian plants

Toxic metabolites that could promote the formation of tumors are generated with high levels of β-glucuronidase activities. Hence, the inhibition of the β-glucuronidase enzyme is effective in the prevention of colonic carcinogenesis, and other diseases. This study aims to investigate the β-glucuronidase inhibitory effect of compounds that were isolated from Nauclea subdita (Korth.) Steud. and Alpinia pahangensis Ridley, together with their mode of inhibition, and their interactions with the enzyme. Angustine (1) and (E)-labda-8 (17),12-dien-15,16-dial (2) are secondary metabolites which were isolated from Nauclea subdita (Korth.) Steud. and Alpinia pahangensis Ridley, respectively. Both exhibited potent inhibitory activities against the β-glucuronidase enzyme with IC50 values of 5.6 ± 0.70 and 23.61 ± 3.32 μM, respectively. The enzyme kinetic studies suggested that compounds 1 and 2 were non-competitive inhibitors with inhibition constants (Ki) of 8.46 and 22.0 μM, respectively. In silico molecular docking and molecular dynamics simulation studies showed that the amino acid residues that interacted with compounds 1 and 2 were Phe161, Leu361, Phe448, Tyr468, Tyr472, and Leu561. These amino acid residues interacted with compound 1 with lower energy as compared to compound 2. Furthermore, the binding free energy of compound 1 (GBTOT value of −31.69 kcal mol−1) was found to be lower than that of compound 2 (GBTOT value of −22.32 kcal mol−1). Compound 1 was thus predicted to be a more active inhibitor through in silico molecular docking and molecular dynamics simulation studies.

Isolation and Structural Characterization of Specific Bacterial β-Glucuronidase Inhibitors from Noni (Morinda citrifolia) Fruits.

An extract of noni (Morinda citrifolia) fruits has shown potent inhibitory activity on gut bacterial β-glucuronidase, which could help reduce irinotecan-induced diarrhea. In this study, four bacterial β-glucuronidase inhibitors were obtained following bioactive assay-guided isolation, including two sesquineolignans, (7S,8S,7'R,8'R)-isoamericanol B (1) and americanol B (2), and two dineolignans, moricitrins A (3) and B (4). Compounds 2-4 are new, and the absolute configuration of compound 1 was determined for the first time. Their chemical structures were elucidated through HRESIMS and NMR spectra, and their absolute configurations were established via the comparison of the experimental and calculated electronic circular dichroism spectra. These compounds showed potent inhibition against gut bacterial β-glucuronidase with IC50 values in the range 0.62-6.91 μM. The inhibition presented specificity for β-glucuronidase, as all the compounds showed no or weak effects on digestive enzymes such as α-amylase, α-glucosidase, and lipase, suggesting that their gastrointestinal side effects could be minimized. These specific inhibitors as naturally occurring dietary compounds may be developed as promising candidates to alleviate irinotecan-induced diarrhea.

New planar assay for streamlined detection and quantification of β-glucuronidase inhibitors applied to botanical extracts

The inhibition of the β-glucuronidase released from gut bacteria is associated with specific health-related benefits. Though a number of β-glucuronidase inhibition assays are currently in use, none of them can directly measure the relevant activity of each single constituent in a complex mixture, without prior separation and tedious isolation of the pure compounds. Thus, the hyphenation of the high performance thin layer chromatography (HPTLC) technique with a β-glucuronidase inhibition assay was investigated and successfully demonstrated for the first time. A colorimetric as well as fluorometric detection of the inhibitors was achieved using 5-bromo-4-chloro-3-indolyl-β-D-glucuronide as a substrate. Hence, β-glucuronidase inhibitors were detected as bright zones against an indigo blue or fluorescent background. The established method was optimized and validated employing the well-known inhibitor d-saccharic acid 1,4-lactone monohydrate. As proof of concept, the suitability of the new workflow was verified through analysis of two botanical extracts, Primula boveana and silymarin flavonolignans from Silybum marianum fruits. The found inhibitors were identified by spectroscopic methods; one of them, 3ʹ-O-(β-galactopyranosyl)-flavone, is here described as a newly isolated natural compound. The new hyphenation HPTLC-UV/Vis/FLD-β-glucuronidase inhibition assay-HRMS covers four orthogonal dimensions, i.e. separation, spectral detection, biochemical activity and structural characterization, in a highly targeted time- and material-saving workflow for analysis of complex or costly mixtures.

Thiazolidin-2-cyanamides derivatives as novel potent Escherichia coli β-glucuronidase inhibitors and their structure–inhibitory activity relationships

Gut microbial β-glucuronidases have the ability to deconjugate glucuronides of some drugs, thus have been considered as an important drug target to alleviate the drug metabolites-induced gastrointestinal toxicity. In this study, thiazolidin-2-cyanamide derivatives containing 5-phenyl-2-furan moiety (1–13) were evaluated for inhibitory activity against Escherichia coli β-glucuronidase (EcGUS). All of them showed more potent inhibition than a commonly used positive control, d-saccharic acid 1,4-lactone, with the IC50 values ranging from 1.2 µM to 23.1 µM. Inhibition kinetics studies indicated that compound 1–3 were competitive type inhibitors for EcGUS. Molecular docking studies were performed and predicted the potential molecular determinants for their potent inhibitory effects towards EcGUS. Structure–inhibitory activity relationship study revealed that chloro substitution on the phenyl moiety was essential for EcGUS inhibition, which would help researchers to design and develop more effective thiazolidin-2-cyanamide type inhibitors against EcGUS.

Advances in In-Silico based Predictive In-Vivo Profiling of Novel Potent β-Glucuronidase Inhibitors.

Intestinal β-glucuronidase enzyme has a significant importance in colorectal carcinogenesis. Specific inhibition of the enzyme helps prevent immune reactivation of the glucuronide- carcinogens, thus protecting the intestine from ROS (Reactive Oxidative Species) mediatedcarcinogenesis. Advancement in In-silico based techniques has provided a broad range of studies to carry out the drug design and development process smoothly using SwissADME and BOILED-Egg tools. In our designed case study, we used SwissADME and BOILED-Egg predictive computational tools to estimate the physicochemical, human pharmacokinetics, drug-likeness, medicinal chemistry properties and membrane permeability characteristics of our recently In-vitro evaluated novel β-Glucuronidase inhibitors. Out of the eleven screened potent inhibitors, compound (8) exhibited excellent bioavailability radar against the six molecular descriptors, good (ADME) Absorption, Distribution, Metabolism and Excretion along with P-glycoprotein, CYP450 isozymes and membranes permeability profile. On the basis of these factual observations, it is to be predicted that compound (8) can achieve in-vivo experimental clearance efficiently, Therefore, in the future, it can be a drug in the market to treat various disorders associated with the overexpression of β-Glucuronidase enzyme such as various types of cancer, particularly hormone-dependent cancer such as (breast, prostate, and colon cancer). Moreover, other compounds (1-7, & 9-11), have also shown good predictive pharmacokinetics, medicinal chemistry, BBB and HIA membranes permeability profiles with slight lead optimization to obtain improved results. In consequence, in-silico based studies are considered to provide robustness for a rational drug design and development approach to avoid the possibility of failures of drug candidates in the later stages of drug development phases. The results of this study effectively reveal the possible attributes of potent β-Glucuronidase inhibitors, for further experimental evaluation.

Molecular Modelling, Docking and Pharmacokinetic Studies of N-Arylidenequinoline-3-Carbohydrazides Analogs as Novel β-Glucuronidase Inhibitors

Quantitative structure-activity relationships (QSAR) modelling on 30 N-Arylidenequinoline-3-carbohydrazides analogs was performed using Multi-Linear Regression (MLR) analysis adopting Genetic Function Algorithm (GFA) method. Semi empirical method using PM6 basis set was used for complete geometry optimization of the data set. The best model was chosen based on its statistical fit due to it good internal and external validations. From the Williams plot, it can be inferred that the reported model can make prediction of new compounds that are not within the data set. The molecular docking study showed that, the most active chemical in the data set was better than the standard β-glucuronidase inhibitor both in terms of binding scores and the amino acid residues that interacted with the drug and β-glucuronidase enzyme. The Pharmacokinetic studies indicated that none of the chemicals violated any of the condition set by the Lipinski′s Rule of five which confirm the bioavailability of these chemicals. The results these findings give room for designing novel β-glucuronidase inhibitors that are highly effective.
 
 Resumen. Se llevó a cabo la técnica de QSAR en 30 analogos de N-arilidenequinolina-3-carbohidrazidas mediante el analisis de regresesión lineal múltiple (MLS) adopatando el método del algoritmo de función genética (GFA). Para la optimización completa de la geometría del conjunto de datos se utilizó un método semiémpirico del conjunto de bases PM6. El mejor modelo fue elegido basado en función de su ajuste estadístico debido a su validación interna y externa. A partir de la gráfica de Williams, se puede inferir que el modelo reportado puede predecir nuevos compuestos que no se encuentran en el conjunto de datos. Este estudio de acomplamiento molecular mostró que, el químico más activo del conjunto de datos fue mejor que el inhibidor estándar β-glucuronidasa, tanto en términos de unión y en términos de interacción de los residuos con el fármaco y la enzima β-glucuronidasa. Los estudios farmacocinéticos que indicaron que ninguno de los fármacos incumple ninguna de las condiciones establecidas por la regla de cinco de Lipinski, en donde se confirma la biodisponibilidad de estos químicos. Los resultados de los hallazgos computacionales permiten diseñar nuevos inhibidores de la β-glucuronidasa que son altamente efectivos.

The study of inhibitory effect of natural flavonoids toward β-glucuronidase and interaction of flavonoids with β-glucuronidase

β-Glucuronidase plays a vital role in the metabolism of drugs and endogenous substance. Herein, we assayed the inhibitory effects of thirty-six flavonoids (1–36) toward β-glucuronidase (Escherichia coli) using the probe reaction of DDAO-glu hydrolysis. The results showed that kushenol X (6), (2S)-farrerol (10), 5,7,2′-trihydroxy-8,6′-dimethoxy flavone (20), demethylbellidifolin (31), and gentisin (32) exhibited potent inhibitory activities toward β-glucuronidase with the IC50 values of 2.07 ± 0.26, 8.95 ± 0.74, 4.97 ± 0.61, 0.91 ± 0.11, and 0.68 ± 0.10 μM, respectively. Furthermore, the inhibition kinetics studies indicated that demethylbellidifolin (31) and gentisin (32) exhibited mixed-type inhibiton toward β-glucuronidase, the Ki values were caculated to be 4.05 and 2.02 μM, respectively. Additionally, the circular change of dichroism (CD) spectrum verified the interaction between demethylbellidifolin (31) and gentisin (32) with β-glucuronidase; following by the molecular docking and molecular dynamics further revealed the potential interaction amino acid site in β-glucuronidase. All our findings not only developed some potent novel β-glucuronidase inhibitors but also indicated the potential herb drug interaction (HDI) effects of flavonoids with some clinical drugs which had enterohepatic circulation and further revealed the vital pharamcophoric requirement of natural flavonoids for β-glucuronidase inhibition activity.

Correction to Highly Selective NIR Probe for Intestinal β-Glucuronidase and High-Throughput Screening Inhibitors to Therapy Intestinal Damage.

β-Glucuronidase (GLU) as a vital factor in enterohepatic circulation and drug-inducing enteropathy has been given more and more attention in recent years. In this study, an off–on near-infrared (NIR) fluorescent probe (DDAO-glu) for selectively and sensitively sensing GLU was developed on the basis of its substrate preference. DDAO-glu can rapidly and selectively respond to bacterial GLU under physiological conditions for detecting the real-time intestinal GLU bioactivity of complex biological systems such as human feces in clinic. Meantime, DDAO-glu has been successfully applied for visualization of endogenous GLU in bacterial biofilm, thallus, and even in vivo. Using this NIR probe, we successfully visualized the real distribution of intestinal GLU in the enterohepatic circulation. Furthermore, a high-throughput screening method was successfully established by our probe, and a potent natural inhibitor of GLU was identified as (−)-epicatechin-3-gallate (ECG) for effectively preventing NSAIDs-inducing ent...

2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis, in vitro and in silico studies

Twenty-five thiadiazole derivatives 1–25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC50 = 26.05 ± 0.60 μM), 2 (IC50 = 42.53 ± 0.80 μM), 4 (IC50 = 38.74 ± 0.70 μM), 5 (IC50 = 9.30 ± 0.29 μM), 6 (IC50 = 6.74 ± 0.26 μM), 7 (IC50 = 18.40 ± 0.66 μM), and 15 (IC50 = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d-saccharic acid-1,4-lactone (IC50 = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.

Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent β-glucuronidase inhibitors and their molecular docking study.

A new series of oxadiazole with thiadiazole moiety (6-27) were synthesized, characterized by different spectroscopic techniques and evaluated for β-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC50 values in the range of 0.96 ± 0.01 to 46.46 ± 1.10 μM, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 μM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent β-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition.

Synthesis of Chromen-4-One-Oxadiazole Substituted Analogs as Potent β-Glucuronidase Inhibitors

Chromen-4-one substituted oxadiazole analogs 1–19 have been synthesized, characterized and evaluated for β-glucuronidase inhibition. All analogs exhibited a variable degree of β-glucuronidase inhibitory activity with IC50 values ranging in between 0.8 ± 0.1–42.3 ± 0.8 μM when compared with the standard d-saccharic acid 1,4 lactone (IC50 = 48.1 ± 1.2 μM). Structure activity relationship has been established for all compounds. Molecular docking studies were performed to predict the binding interaction of the compounds with the active site of enzyme.

Bioinformatics: A rational combine approach used for the identification and in-vitro activity evaluation of potent β-Glucuronidase inhibitors

Identification of hotspot drug-receptor interactions through in-silico prediction methods (Pharmacophore mapping, virtual screening, 3DQSAR, etc), is considered as a key approach in drug designing and development process. In the current design study, advanced in-silico based computational techniques were used for the identification of lead-like molecules against the targeted receptor β-glucuronidase. The binding pattern of a potent inhibitor in the ligand-receptor X-ray co-crystallize complex was used to identify and extract the structure-base Pharmacophore features. Based on these observations; five structure-based pharmacophore models were derived to conduct the virtual screening of ICCBS in-house data-base. Top-ranked identified Hits (33 compounds) were selected to subject for in-vitro biological activity evaluation against β-glucuronidase enzyme; out of them, twenty compounds (61% of screened compounds) evaluated as actives, however eleven compounds were found to have significantly higher inhibitory activity, including compounds 1, 5–8, 10, 12–13, and 17–19 with IC50 values ranging from 1.2 μM to 34.9 μM. Out of the eleven potent inhibitors, seven compounds 1, 5, 6, 7, 8, 13, and 19 were found new, and evaluated first time for the β-glucuronidase inhibitory activity. Compounds 1, 5 and 19 exhibited a highly potent inhibition in uM of β-glucuronidase enzyme with non-cytotoxic behavior against the mouse fibroblast (3T3) cell line. Our combined in-silico and in-vitro results revealed that the binding pattern analysis of the eleven potent inhibitors, showed almost similar non-covalent interactions, as observed in case of our validated pharmacophore model. The obtained results thus demonstrated that the virtual screening minimizes false positives, and provide a template for the identification and development of new and more potent β-glucuronidase inhibitors with non-toxic effects.

2-Oxo-1,2,3,4-tetrahydropyrimidines Ethyl Esters as Potent β- Glucuronidase Inhibitors: One-pot Synthesis, In vitro and In silico Studies.

Glucuronidation is essential for the metabolism and excretion of toxic substances. β-Glucuronidase enzyme slows down the process of glucuronidation, and thus plays an important role in the on-set of colorectal carcinoma, and many other diseases. Inhibition of β- glucuronidase activity is thus identified as an important approach for the treatment of several diseases. Current study was aimed to synthesize a library of 2-oxo-1,2,3,4-tetrahydropyrimidine and to evaluate their β-glucuronidase inhibitory activity, and their mode of enzyme inhibition. We synthesized a series of 2-oxo-1,2,3,4-tetrahydropyrimidines 1-25 by fusing urea, ethyl acetoacetate, and a variety of aldehydes using copper nitrate trihydrate as catalyst. All synthesized compounds were evaluated for their in vitro β-glucuronidase inhibitory activity. In addition, molecular docking studies were also performed by using MOE docking tools. Eighteen compounds showed inhibitory activity better than the standard D-saccharic acid 1,4-lactone, a well known β-glucuronidase inhibitor (IC50 = 45.75 ± 2.16 µM). Compound 20 (IC50 = 1.36 ± 0.03 µM) showed an excellent inhibitory activity, thirty-five folds superior to the standard. Docking results highlighted the role of various chemical moieties at different positions on 2- oxo-1,2,3,4-tetrahydropyrimidine skeleton in enzyme inhibitory activity. This study has identified a class of potent β-glucuronidase inhibitors with the potential to be investigated further.

Highly Selective NIR Probe for Intestinal β-Glucuronidase and High-Throughput Screening Inhibitors to Therapy Intestinal Damage.

β-Glucuronidase (GLU) as a vital factor in enterohepatic circulation and drug-inducing enteropathy has been given more and more attention in recent years. In this study, an off-on near-infrared (NIR) fluorescent probe (DDAO-glu) for selectively and sensitively sensing GLU was developed on the basis of its substrate preference. DDAO-glu can rapidly and selectively respond to bacterial GLU under physiological conditions for detecting the real-time intestinal GLU bioactivity of complex biological systems such as human feces in clinic. Meantime, DDAO-glu has been successfully applied for visualization of endogenous GLU in bacterial biofilm, thallus, and even in vivo. Using this NIR probe, we successfully visualized the real distribution of intestinal GLU in the enterohepatic circulation. Furthermore, a high-throughput screening method was successfully established by our probe, and a potent natural inhibitor of GLU was identified as (-)-epicatechin-3-gallate (ECG) for effectively preventing NSAIDs-inducing enteropathy in vivo. DDAO-glu could serve as a powerful tool for exploring real physical functions of intestinal GLU in enterohepatic circulation, under physiological and pathological contexts, and developing the novel inhibitors of GLU to therapy acute drug-inducing enteropathy in clinic.

Prenylflavonoids sanggenon C and kuwanon G from mulberry (Morus alba L.) as potent broad-spectrum bacterial β-glucuronidase inhibitors: Biological evaluation and molecular docking studies

Gut microbial β-glucuronidases show varied substrate specificity and inhibition propensity, highlighting the necessity of discovering broad-spectrum β-glucuronidase inhibitor to meet clinical needs. In this study, two prenylflavonoids sanggenon C (SGC) and kuwanon G (KWG) exhibited strong inhibition on p-nitrophenyl-β-D-glucuronide-hydrolyzing activity in pooled human gut microbiota and eight bacterial isolates, while amoxapine, a previously reported Escherichia coli β-glucuronidase (EcoGUS) inhibitor, only showed poor inhibition on the pooled samples and relatively selective inhibition on individual strains with incomplete inhibition on Staphylococcus.pasteuri 3I10. Both prenylflavonoids exhibited mixed-type inhibition against the recombinant enzymes EcoGUS and S. pasteuri 3I10 β-glucuronidase (SpasGUS). Molecular docking studies predicted phenolic groups of SGC and KWG as key structures interacting with the allosteric site of SpasGUS, while the phenolic hydroxyl (SGC) or benzopyranyl (KWG) group accounts for the hydrogen bond interaction with EcoGUS. The potentials of these broad-spectrum inhibitors in alleviating bacterial β-glucuronidase-mediated drug toxicity/efficacy warrants further investigation.

Synthesis: Small library of hybrid scaffolds of benzothiazole having hydrazone and evaluation of their β-glucuronidase activity

Due to the great biological importance of β-glucuronidase inhibitors, here in this study, we have synthesized a library of novel benzothiazole derivatives (1–30), characterized by different spectroscopic methods and evaluated for β-glucuronidase inhibitory potential. Among the series sixteen compounds i.e.1–6, 8, 9, 11, 14, 15, 20–23 and 26 showed outstanding inhibitory potential with IC50 value ranging in between 16.50 ± 0.26 and 59.45 ± 1.12 when compared with standard d-Saccharic acid 1,4-lactone (48.4 ± 1.25 µM). Except compound 8 and 23 all active analogs showed better potential than the standard. Structure activity relationship has been established.

Isogloiosiphone B, a novel acetal, and hydrophobic compounds as β-glucuronidase inhibitors derived from the red alga Neodilsea yendoana.

A novel acetal named isogloiosiphone B was isolated from the red alga Neodilsea yendoana, along with three known hydrophobic compounds as β-glucuronidase inhibitors. The acetal was determined as a naturally occurring compound from the extraction experiments with several kinds of solvent. The acetal showed the highest inhibition against β-glucuronidase among the compounds examined.

Synthesis of bis-indolylmethanes as new potential inhibitors of β-glucuronidase and their molecular docking studies

Thirty-two (32) bis-indolylmethane-hydrazone hybrids 1–32 were synthesized and characterized by 1HNMR, 13CNNMR and HREI-MS. All compounds were evaluated in vitro for β-glucuronidase inhibitory potential. All analogs showed varying degree of β-glucuronidase inhibitory potential ranging from 0.10 ± 0.01 to 48.50 ± 1.10 μM when compared with the standard drug d-saccharic acid-1,4-lactone (IC50 value 48.30 ± 1.20 μM). Derivatives 1–32 showed the highest β-glucuronidase inhibitory potentials which is many folds better than the standard drug d-saccharic acid-1,4-lactone. Further molecular docking study validated the experimental results. It was proposed that bis-indolylmethane may interact with some amino acid residues located within the active site of β-glucuronidase enzyme. This study has culminated in the identification of a new class of potent β-glucuronidase inhibitors.