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5. Thiazolide Prodrug Esters and Derived Peptides: Synthesis and Activity

Author

Stachulski, Andrew V., primary, Rossignol, Jean-Francois, additional, Pate, Sophie, additional, Taujanskas, Joshua, additional, Iggo, Jonathan A., additional, Aerts, Rudi, additional, Pascal, Etienne, additional, Piacentini, Sara, additional, La Frazia, Simone, additional, Santoro, M. Gabriella, additional, van Vooren, Lieven, additional, Sintubin, Liesje, additional, Cooper, Mark, additional, Swift, Karl, additional, and O’Neill, Paul M., additional

Published
2023
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6. Cerebrovascular damage caused by the gut microbe-derived uraemic toxinp-cresol sulfate is prevented by blockade of the epidermal growth factor receptor

Author

Shah, Sita N, primary, Knausenberger, Tobias B-A, additional, Connell, Emily, additional, Gall, Gwenaelle Le, additional, Hardy, Tom A. J., additional, Randall, David W., additional, McCafferty, Kieran, additional, Yaqoob, Muhammad M., additional, Solito, E., additional, Müller, Michael, additional, Stachulski, Andrew V., additional, Glen, Robert C., additional, Vauzour, David, additional, Hoyles, Lesley, additional, and McArthur, Simon, additional

Published
2022
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12. A host–gut microbial amino acid co-metabolite, p-cresol glucuronide, promotes blood–brain barrier integrity in vivo.

Author

Stachulski, Andrew V., Knausenberger, Tobias B-A, Shah, Sita N., Hoyles, Lesley, and McArthur, Simon

Subjects
*MICROBIAL metabolites, *MICROBIAL enzymes, *BLOOD-brain barrier, *AMINO acids, *AMINO acid metabolism, *PERMEABILITY, *LIPOPOLYSACCHARIDES
Abstract

The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Male C57Bl/6 J mice were used to assess blood–brain barrier (BBB) permeability and whole-brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Mice exposed to pCG showed reduced BBB permeability and significant changes in whole-brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilizing effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. The amino acid phase II metabolic product pCG is biologically active at the BBB, antagonizing the effects of constitutively circulating lipopolysaccharide. These data add to the growing literature showing glucuronide conjugates to be more than merely metabolic waste products and highlight the complexity of gut microbe to host communication pathways underlying the gut–brain axis. [ABSTRACT FROM AUTHOR]

Published
2023
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13. Synthesis, antiviral activity, preliminary pharmacokinetics and structural parameters of thiazolide amine salts

Author

Stachulski, Andrew V, primary, Rossignol, Jean-Francois, additional, Pate, Sophie, additional, Taujanskas, Joshua, additional, Robertson, Craig M, additional, Aerts, Rudi, additional, Pascal, Etienne, additional, Piacentini, Sara, additional, Frazia, Simone La, additional, Santoro, M Gabriella, additional, and O’Neill, Paul M, additional

Published
2021
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14. Discovery and Optimization of a 4-Aminopiperidine Scaffold for Inhibition of Hepatitis C Virus Assembly

Author

Rolt, Adam, primary, Talley, Daniel C., additional, Park, Seung Bum, additional, Hu, Zongyi, additional, Dulcey, Andrés, additional, Ma, Christopher, additional, Irvin, Parker, additional, Leek, Madeleine, additional, Wang, Amy Q., additional, Stachulski, Andrew V., additional, Xu, Xin, additional, Southall, Noel, additional, Ferrer, Marc, additional, Liang, T. Jake, additional, and Marugan, Juan J., additional

Published
2021
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15. Cerebrovascular damage caused by the gut microbe/host co-metabolite p-cresol sulfate is prevented by blockade of the EGF receptor

Author

Shah, Sita N., Knausenberger, Tobias B-A., Pontifex, Matthew G., Connell, Emily, Le Gall, Gwénaëlle, Hardy, Tom A.J., Randall, David W., McCafferty, Kieran, Yaqoob, Muhammad M., Solito, Egle, Müller, Michael, Stachulski, Andrew V., Glen, Robert C., Vauzour, David, Hoyles, Lesley, and McArthur, Simon

Abstract

ABSTRACTThe gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood–brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitroand both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitroand in vivomechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitroled to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.

Published
2024
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16. Kinetic and J-resolved statistical total correlation NMR spectroscopy approaches to structural information recovery in complex reacting mixtures: application to acyl glucuronide intramolecular transacylation reactions

Author

Johnson, Caroline H., Athersuch, Toby J., Wilson, Ian D., Iddon, Lisa, Meng, Xiaoli, Stachulski, Andrew V., Lindon, John C., and Nicholson, Jeremy K.

Subjects
Mixtures -- Properties, Acylation -- Research, Nuclear magnetic resonance spectroscopy -- Methods, Chemistry
Abstract

We demonstrate here a new variant on a statistical spectroscopic method for recovering structural information on unstable intermediates formed in reaction mixtures. We exemplify this approach with respect to the internal acyl migration reactions of 1-[beta]-O-acyl glucuronides (AGs), which rearrange at neutral or slightly alkaline pH on a minute to hour time scale to yield a series of positional glucuronide ring isomers and [alpha]/[beta] anomers from the 1-[beta] (starting material), i.e. 2-[beta], 2-[alpha], l-[alpha], 3-[beta], 3-[alpha], and 4-[beta], 4-[alpha] isomers together with the aglycon and [alpha]- and [beta]-glucuronic acid hydrolysis products. Multiple sequential 800 MHz cryoprobe [sup.1]H NMR spectra (1D and 2D J-resolved, JRES) were collected on a 5.1 mM solution of a synthetic model drug glucuronide, 1-[beta]-O-acyl (S)-alpha]-methyl phenylacetyl glucuronide (MPG) in 0.1 M sodium phosphate buffer in [D.sub.2]O at pD 7.4 over 18 h to monitor the reaction which leads to the formation of the eight positional isomers and hydrolysis products. As the reaction proceeds and new isomers form, the NMR signal intensities vary accordingly allowing the application of a novel kinetic variant on statistical total correlation spectroscopy (K-STOCSY) method to recover the connectivities between proton signals on the same reacting molecule based on their intensity covariance through time. We performed K-STOCSY analysis on both the standard 1D NMR spectra and the skyline projected singlets of the [sup.1]H-[sup.1]H JRES NMR spectra through time, i.e. the K-JRES-STOCSY experimental variant, which increases the effective spectral dispersion and is ideally suited for the analysis of heavily overlapped spin systems. High statistical correlations were observed between mutarotated [alpha]-and [beta]-anomers of individual positional isomers, as well as directly acyl migrated products and anticorrelation observed between signals from compounds that were being depleted as others increased, e.g. between the 1-[beta] and 2-[alpha]/2-[beta] isomers. This statistical kinetic approach enabled the recovery of structural connectivity information on all isomers allowing unequivocal resonance assignment, and this approach to spectroscopic information recovery has wider potential uses in the study of reactions that occur on the second-to-minute time scale in conditions where multiple sequential NMR spectra can be collected. JRES-STOCSY is also of potential use as a method for recovering spectroscopic information in highly overlapped NMR signals and spin systems in other types of complex mixture analysis.

Published
2008

17. NMR spectroscopic studies on the in vitro acyl glucuronide migration kinetics of ibuprofen (([+ or -])-(R,S)-2-(4-Isobutylphenyl) propanoic acid), its metabolites, and analogues

Author

Johnson, Caroline H., Wilson, Ian D., Harding, John R., Stachulski, Andrew V., Iddon, Lisa, Nicholson, Jeremy K., and Lindon, John C.

Subjects
Metabolites -- Properties, Ibuprofen -- Properties, Nuclear magnetic resonance -- Methods, Hydrolysis -- Measurement, Chemistry
Abstract

Carboxylic acid-containing drugs are often metabolized to 1-[beta]-O-acyl glucuronides (AGs). These can undergo an internal chemical rearrangement, and the resulting reactive positional isomers can bind to endogenous proteins, with clear potential for adverse effects. Additionally any 1-[beta]-O-acyl-glucuronidated phase I metabolite of the drug can also show this propensity, and investigation of the adverse effect potential of a drug also needs to consider such metabolites. Here the transacylation of the common drug ibuprofen and two of its metabolites is investigated in vitro. 1-[beta]-O-Acyl (S)-ibuprofen glucuronide was isolated from human urine and also synthesized by selective acylation. Urine was also used as a source of the (R)ibuprofen, (S)-2-hydroxyibuprofen, and (S,S)-carboxyibuprofen AGs. The degradation rates (a combination of transacylation and hydrolysis) were measured using [sup.1]H NMR spectroscopy, and the measured decrease in the 1-[beta] anomer over time was used to derive half-lives for the glucuronides. The biosynthetic and chemically synthesized (S)-ibuprofen AGs had half-lives of 3.68 and 3.76 h, respectively. (R)-Ibuprofen AG had a half-life of 1.79 h, a value approximately half that of the (S)-diastereoisomer, consistent with results from other 2-aryl propionic acid drug AGs. The 2-hydroxyibuprofen and carboxyibuprofen AGs gave half-lives of 5.03 and 4.80 h, considerably longer than that of either of the parent drug glucuronides. In addition, two (S)-ibuprofen glucuronides were synthesized with the glucuronide carboxyl function esterified with either ethyl or allyl groups. The (S)-ibuprofen AG ethyl ester and (S)-ibuprofen AG allyl esters were determined to have half-lives of 7.24 and 9.35 h, respectively. In order to construct useful structure-reactivity relationships, it is necessary to evaluate transacylation and hydrolysis separately, and here it is shown that the (R)- and (S)-ibuprofen AGs have different transacylation properties. The implications of these findings are discussed in terms of structure-activity relationships.

Published
2007

22. Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2?

Author

Stachulski, Andrew V., primary, Taujanskas, Joshua, additional, Pate, Sophie L., additional, Rajoli, Rajith K. R., additional, Aljayyoussi, Ghaith, additional, Pennington, Shaun H., additional, Ward, Stephen A., additional, Hong, Weiqian David, additional, Biagini, Giancarlo A., additional, Owen, Andrew, additional, Nixon, Gemma L., additional, Leung, Suet C., additional, and O’Neill, Paul M., additional

Published
2020
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23. Drug metabolism: the body's defense against chemical attack

Author

Stachulski, Andrew V. and Lennard, Martin S.

Subjects
Drug metabolism -- Physiological aspects, Biochemistry -- Physiological aspects, Molecules -- Models, Enzymes -- Physiological aspects, Drugs -- Physiological aspects, Grapefruit -- Physiological aspects, Cytochrome P-450 -- Physiological aspects, Chemistry, Education, Science and technology
Abstract

Drug metabolism, using body enzymes, and clinical and industrial implications are discussed. The cytochrome P450 monooxygenases (CYPs) are largely repsonsible for drug oxidation. The organic chemist can play a role in the synthesis of drug substrates, metabolites and inhibitors needed for experimental studies. Molecular modeling, paracetamol, terfenadine, dietary flavonoids, such as those found in grapefruit, and morphine-6-glucuronide are discussed. Future implications for medicinal chemists are considered.

Published
2000

27. Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus

Author

Stachulski, Andrew V., Santoro, M. Gabriella, Piacentini, Sara, Belardo, Giuseppe, La Frazia, Simone, Pidathala, Chandrakala, Row, Eleanor C., Berry, Neil G., Iqbal, Mazhar, Allman, Sarah A., Semple, J.Edward, Eklov, Brian M., O'Neill, Paul M., and Rossignol, Jean-Francois

Subjects
antiviral drugs, Thiazoles, Influenza A Virus, H1N1 Subtype, molecular modeling, Influenza A virus, computational chemistry, drug discovery, Drug Discovery, Influenza, Human, Humans, Settore MED/07 - Microbiologia e Microbiologia Clinica, Nitro Compounds, Antiviral Agents
Abstract

Aim: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. Results: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory-adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14–5.0 μM. Additionally a quantitative structure–property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. Conclusion: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified.

Published
2018

31. Thiazolides as Novel Antiviral Agents: I. Inhibition of Hepatitis B Virus Replication

Author

Stachulski, Andrew V., Pidathala, Chandrakala, Row, Eleanor C., Sharma, Raman, Berry, Neil G., Iqbal, Mazhar, Bentley, Joanne, Allman, Sarah A., Edwards, Geoffrey, Helm, Alison, Hellier, Jennifer, Korba, Brent E., Semple, J. Edward, and Rossignol, Jean-Francois

Subjects
Hepatitis B virus, Virion, Quantitative Structure-Activity Relationship, Hep G2 Cells, In Vitro Techniques, Virus Replication, Amides, Antiviral Agents, Article, Rats, Thiazoles, Dogs, Glucuronides, Salicylamides, Animals, Humans, Prodrugs
Abstract

We report the syntheses and activities of a wide range of thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is a broad spectrum antiinfective agent effective against anaerobic bacteria, viruses, and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent, and selective inhibitor of hepatitis B replication (EC(50) = 0.33 μm) but is inactive against anaerobes. Several 4'- and 5'-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1; viz., the O-acetate is an effective prodrug, and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC(90) for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

Published
2011

33. Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

Author

Hammond, Thomas G., primary, Meng, Xiaoli, additional, Jenkins, Rosalind E., additional, Maggs, James L., additional, Castelazo, Anahi Santoyo, additional, Regan, Sophie L., additional, Bennett, Stuart N. L., additional, Earnshaw, Caroline J., additional, Aithal, Guruprasad P., additional, Pande, Ira, additional, Kenna, J. Gerry, additional, Stachulski, Andrew V., additional, Park, B. Kevin, additional, and Williams, Dominic P., additional

Published
2014
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40. The Generation, Detection, and Effects of Reactive Drug Metabolites

Author

Stachulski, Andrew V., primary, Baillie, Thomas A., additional, Kevin Park, B., additional, Scott Obach, R., additional, Dalvie, Deepak K., additional, Williams, Dominic P., additional, Srivastava, Abhishek, additional, Regan, Sophie L., additional, Antoine, Daniel J., additional, Goldring, Christopher E. P., additional, Chia, Alvin J. L., additional, Kitteringham, Neil R., additional, Randle, Laura E., additional, Callan, Hayley, additional, Castrejon, J. Luis, additional, Farrell, John, additional, Naisbitt, Dean J., additional, and Lennard, Martin S., additional

Published
2012
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42. Thiazolides as Novel Antiviral Agents. 2. Inhibition of Hepatitis C Virus Replication

Author

Stachulski, Andrew V., primary, Pidathala, Chandrakala, additional, Row, Eleanor C., additional, Sharma, Raman, additional, Berry, Neil G., additional, Lawrenson, Alexandre S., additional, Moores, Shelley L., additional, Iqbal, Mazhar, additional, Bentley, Joanne, additional, Allman, Sarah A., additional, Edwards, Geoffrey, additional, Helm, Alison, additional, Hellier, Jennifer, additional, Korba, Brent E., additional, Semple, J. Edward, additional, and Rossignol, Jean-Francois, additional

Published
2011
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44. Direct Evidence for the Formation of Diastereoisomeric Benzylpenicilloyl Haptens from Benzylpenicillin and Benzylpenicillenic Acid in Patients

Author

Meng, Xiaoli, primary, Jenkins, Rosalind E., additional, Berry, Neil G., additional, Maggs, James L., additional, Farrell, John, additional, Lane, Catherine S., additional, Stachulski, Andrew V., additional, French, Neil S., additional, Naisbitt, Dean J., additional, Pirmohamed, Munir, additional, and Park, B. Kevin, additional

Published
2011
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45. Thiazolides as Novel Antiviral Agents. 1. Inhibition of Hepatitis B Virus Replication

Author

Stachulski, Andrew V., primary, Pidathala, Chandrakala, additional, Row, Eleanor C., additional, Sharma, Raman, additional, Berry, Neil G., additional, Iqbal, Mazhar, additional, Bentley, Joanne, additional, Allman, Sarah A., additional, Edwards, Geoffrey, additional, Helm, Alison, additional, Hellier, Jennifer, additional, Korba, Brent E., additional, Semple, J. Edward, additional, and Rossignol, Jean-Francois, additional

Published
2011
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48. High‐performance liquid chromatography/mass spectrometric and proton nuclear magnetic resonance spectroscopic studies of the transacylation and hydrolysis of the acyl glucuronides of a series of phenylacetic acids in buffer and human plasma

Author

Karlsson, Elin S., primary, Johnson, Caroline H., additional, Sarda, Sunil, additional, Iddon, Lisa, additional, Iqbal, Mazhar, additional, Meng, Xiaoli, additional, Harding, John R., additional, Stachulski, Andrew V., additional, Nicholson, Jeremy K., additional, Wilson, Ian D., additional, and Lindon, John C., additional

Published
2010
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