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33 results on '"Cleghorn, Laura A. T."'

1. Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Author

Green, Simon R., Davis, Susan H., Damerow, Sebastian, Engelhart, Curtis A., Mathieson, Michael, Baragaña, Beatriz, Robinson, David A., Tamjar, Jevgenia, Dawson, Alice, Tamaki, Fabio K., Buchanan, Kirsteen I., Post, John, Dowers, Karen, Shepherd, Sharon M., Jansen, Chimed, Zuccotto, Fabio, Gilbert, Ian H., Epemolu, Ola, Riley, Jennifer, Stojanovski, Laste, Osuna-Cabello, Maria, Pérez-Herrán, Esther, Rebollo, María José, Guijarro López, Laura, Casado Castro, Patricia, Camino, Isabel, Kim, Heather C., Bean, James M., Nahiyaan, Navid, Rhee, Kyu Y., Wang, Qinglan, Tan, Vee Y., Boshoff, Helena I. M., Converse, Paul J., Li, Si-Yang, Chang, Yong S., Fotouhi, Nader, Upton, Anna M., Nuermberger, Eric L., Schnappinger, Dirk, Read, Kevin D., Encinas, Lourdes, Bates, Robert H., Wyatt, Paul G., and Cleghorn, Laura A. T.

Published
2022
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2. Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static–Cidal Screening of Analogues

Author

Cleghorn, Laura A. T., primary, Wall, Richard J., additional, Albrecht, Sébastien, additional, MacGowan, Stuart A., additional, Norval, Suzanne, additional, De Rycker, Manu, additional, Woodland, Andrew, additional, Spinks, Daniel, additional, Thompson, Stephen, additional, Patterson, Stephen, additional, Corpas Lopez, Victoriano, additional, Dey, Gourav, additional, Collie, Iain T., additional, Hallyburton, Irene, additional, Kime, Robert, additional, Simeons, Frederick R. C., additional, Stojanovski, Laste, additional, Frearson, Julie A., additional, Wyatt, Paul G., additional, Read, Kevin D., additional, Gilbert, Ian H., additional, and Wyllie, Susan, additional

Published
2023
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5. Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosis Inhibitors, Targeting QcrB

Author

Cleghorn, Laura A T, Ray, Peter C, Odingo, Joshua, Kumar, Anuradha, Wescott, Heather, Korkegian, Aaron, Masquelin, Thierry, Lopez Moure, Abraham, Wilson, Caroline, Davis, Susan, Huggett, Margaret, Turner, Penelope, Smith, Alasdair, Epemolu, Ola, Zuccotto, Fabio, Riley, Jennifer, Scullion, Paul, Shishikura, Yoko, Ferguson, Liam, Rullas, Joaquin, Guijarro, Laura, Read, Kevin D, Green, Simon R, Hipskind, Phil, Parish, Tanya, and Wyatt, Paul G

Subjects
Mice, Structure-Activity Relationship, Morpholines, Chlorocebus aethiops, Antitubercular Agents, Animals, Cytochromes c, Mycobacterium tuberculosis, Thiophenes, Oxidoreductases, Vero Cells, Article, Cercopithecus aethiops
Abstract

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosis there is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino-thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis strain H37Rv. The design, synthesis, and structure-activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome c oxidoreductase, part of the bc1-aa3-type cytochrome c oxidase complex that is responsible for driving oxygen-dependent respiration.

Published
2018

6. Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth

Author

Ray, Peter C., primary, Huggett, Margaret, additional, Turner, Penelope A., additional, Taylor, Malcolm, additional, Cleghorn, Laura A. T., additional, Early, Julie, additional, Kumar, Anuradha, additional, Bonnett, Shilah A., additional, Flint, Lindsay, additional, Joerss, Douglas, additional, Johnson, James, additional, Korkegian, Aaron, additional, Mullen, Steven, additional, Moure, Abraham L., additional, Davis, Susan H., additional, Murugesan, Dinakaran, additional, Mathieson, Michael, additional, Caldwell, Nicola, additional, Engelhart, Curtis A., additional, Schnappinger, Dirk, additional, Epemolu, Ola, additional, Zuccotto, Fabio, additional, Riley, Jennifer, additional, Scullion, Paul, additional, Stojanovski, Laste, additional, Massoudi, Lisa, additional, Robertson, Gregory T., additional, Lenaerts, Anne J., additional, Freiberg, Gail, additional, Kempf, Dale J., additional, Masquelin, Thierry, additional, Hipskind, Philip A., additional, Odingo, Joshua, additional, Read, Kevin D., additional, Green, Simon R., additional, Wyatt, Paul G., additional, and Parish, Tanya, additional

Published
2021
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7. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Author

Frearson, Julie A., Brand, Stephen, McElroy, Stuart P., Cleghorn, Laura A. T., Smid, Ondrej, Stojanovski, Laste, Price, Helen P., Guther, M. Lucia S., Torrie, Leah S., Robinson, David A., Hallyburton, Irene, Mpamhanga, Chidochangu P., Brannigan, James A., Wilkinson, Anthony J., Hodgkinson, Michael, Hui, Raymond, Qiu, Wei, Raimi, Olawale G., van Aalten, Daan M. F., Brenk, Ruth, Gilbert, Ian H., Read, Kevin D., Fairlamb, Alan H., Ferguson, Michael A. J., Smith, Deborah F., and Wyatt, Paul G.

Published
2010
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8. Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei

Author

Cleghorn, Laura A. T., Albrecht, Sébastien, Stojanovski, Laste, Simeons, Frederick R. J., Norval, Suzanne, Kime, Robert, Collie, Iain T., De Rycker, Manu, Campbell, Lorna, Hallyburton, Irene, Frearson, Julie A., Wyatt, Paul G., Read, Kevin D., and Gilbert, Ian H.

Subjects
Indoles, Trypanosoma brucei brucei, Drug Evaluation, Preclinical, Brain, Mice, Inbred Strains, Stereoisomerism, Chemistry Techniques, Synthetic, Trypanocidal Agents, Article, Disease Models, Animal, Structure-Activity Relationship, Trypanosomiasis, African, parasitic diseases, Drug Discovery, Animals, Female
Abstract

There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe the optimization and characterization of this series. Potent antiproliferative activity was observed. The series demonstrated excellent pharmacokinetic properties, full cures in a stage 1 mouse model of HAT, and a partial cure in a stage 2 mouse model of HAT. Lack of tolerability prevented delivery of a fully curative regimen in the stage 2 mouse model and thus further progress of this series.

Published
2015

9. Correction for Arora et al., “Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis ”

Author

Arora, Kriti, primary, Ochoa-Montaño, Bernardo, additional, Tsang, Patricia S., additional, Blundell, Tom L., additional, Dawes, Stephanie S., additional, Mizrahi, Valerie, additional, Bayliss, Tracy, additional, Mackenzie, Claire J., additional, Cleghorn, Laura A. T., additional, Ray, Peter C., additional, Wyatt, Paul G., additional, Uh, Eugene, additional, Lee, Jinwoo, additional, Barry, Clifton E., additional, and Boshoff, Helena I., additional

Published
2017
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10. Reactive organoallyl species generated from aryl halides and allene: allylation of alpha,beta-unsaturated aldehydes and cyclic ketones employing Pd/In transmetallation processes

Author

Cleghorn, Laura A. T., Cleghorn, Laura A. T., Grigg, Ronald, Savić, Vladimir, Simić, Milena, Cleghorn, Laura A. T., Cleghorn, Laura A. T., Grigg, Ronald, Savić, Vladimir, and Simić, Milena

Abstract

Allylation of alpha,beta-unsaturated aldehydes and cyclic ketones promoted by Pd/In transmetallation processes has been Studied. The unsaturated aldehydes underwent regioselective 1,2-addition to afford secondary homoally alcohols. The reactions have been performed using Pd(OAc)(2)/PPh(3) as catalytic system and metallic indium affording the products in good yields. The same transformation with unsaturated ketones proved to be less efficient, while saturated cyclic ketones delivered generally excellent yields in the presence of Cul. In these latter processes the presence of a distal heteroatom influences the reaction rate.

Published
2008

11. Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis

Author

Park, Yumi, primary, Pacitto, Angela, additional, Bayliss, Tracy, additional, Cleghorn, Laura A. T., additional, Wang, Zhe, additional, Hartman, Travis, additional, Arora, Kriti, additional, Ioerger, Thomas R., additional, Sacchettini, Jim, additional, Rizzi, Menico, additional, Donini, Stefano, additional, Blundell, Tom L., additional, Ascher, David B., additional, Rhee, Kyu, additional, Breda, Ardala, additional, Zhou, Nian, additional, Dartois, Veronique, additional, Jonnala, Surendranadha Reddy, additional, Via, Laura E., additional, Mizrahi, Valerie, additional, Epemolu, Ola, additional, Stojanovski, Laste, additional, Simeons, Fred, additional, Osuna-Cabello, Maria, additional, Ellis, Lucy, additional, MacKenzie, Claire J., additional, Smith, Alasdair R. C., additional, Davis, Susan H., additional, Murugesan, Dinakaran, additional, Buchanan, Kirsteen I., additional, Turner, Penelope A., additional, Huggett, Margaret, additional, Zuccotto, Fabio, additional, Rebollo-Lopez, Maria Jose, additional, Lafuente-Monasterio, Maria Jose, additional, Sanz, Olalla, additional, Diaz, Gracia Santos, additional, Lelièvre, Joël, additional, Ballell, Lluis, additional, Selenski, Carolyn, additional, Axtman, Matthew, additional, Ghidelli-Disse, Sonja, additional, Pflaumer, Hannah, additional, Bösche, Markus, additional, Drewes, Gerard, additional, Freiberg, Gail M., additional, Kurnick, Matthew D., additional, Srikumaran, Myron, additional, Kempf, Dale J., additional, Green, Simon R., additional, Ray, Peter C., additional, Read, Kevin, additional, Wyatt, Paul, additional, Barry, Clifton E., additional, and Boshoff, Helena I., additional

Published
2016
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12. Discovery of Inhibitors ofTrypanosoma bruceiby Phenotypic Screening of a Focused Protein Kinase Library

Author

Woodland, Andrew, primary, Thompson, Stephen, additional, Cleghorn, Laura A. T., additional, Norcross, Neil, additional, De Rycker, Manu, additional, Grimaldi, Raffaella, additional, Hallyburton, Irene, additional, Rao, Bhavya, additional, Norval, Suzanne, additional, Stojanovski, Laste, additional, Brun, Reto, additional, Kaiser, Marcel, additional, Frearson, Julie A., additional, Gray, David W., additional, Wyatt, Paul G., additional, Read, Kevin D., additional, and Gilbert, Ian H., additional

Published
2015
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13. Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis

Author

Arora, Kriti, primary, Ochoa-Montaño, Bernardo, additional, Tsang, Patricia S., additional, Blundell, Tom L., additional, Dawes, Stephanie S., additional, Mizrahi, Valerie, additional, Bayliss, Tracy, additional, Mackenzie, Claire J., additional, Cleghorn, Laura A. T., additional, Ray, Peter C., additional, Wyatt, Paul G., additional, Uh, Eugene, additional, Lee, Jinwoo, additional, Barry, Clifton E., additional, and Boshoff, Helena I., additional

Published
2014
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14. Identification of Morpholino Thiophenes as Novel Mycobacterium tuberculosisInhibitors, Targeting QcrB

Author

Cleghorn, Laura A. T., Ray, Peter C., Odingo, Joshua, Kumar, Anuradha, Wescott, Heather, Korkegian, Aaron, Masquelin, Thierry, Lopez Moure, Abraham, Wilson, Caroline, Davis, Susan, Huggett, Margaret, Turner, Penelope, Smith, Alasdair, Epemolu, Ola, Zuccotto, Fabio, Riley, Jennifer, Scullion, Paul, Shishikura, Yoko, Ferguson, Liam, Rullas, Joaquin, Guijarro, Laura, Read, Kevin D., Green, Simon R., Hipskind, Phil, Parish, Tanya, and Wyatt, Paul G.

Abstract

With the emergence of multidrug-resistant strains of Mycobacterium tuberculosisthere is a pressing need for new oral drugs with novel mechanisms of action. Herein, we describe the identification of a novel morpholino–thiophenes (MOT) series following phenotypic screening of the Eli Lilly corporate library against M. tuberculosisstrain H37Rv. The design, synthesis, and structure–activity relationships of a range of analogues around the confirmed actives are described. Optimized leads with potent whole cell activity against H37Rv, no cytotoxicity flags, and in vivo efficacy in an acute murine model of infection are described. Mode-of-action studies suggest that the novel scaffold targets QcrB, a subunit of the menaquinol cytochrome coxidoreductase, part of the bc1-aa3-type cytochrome coxidase complex that is responsible for driving oxygen-dependent respiration.

Published
2018
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15. Back Cover: From On-Target to Off-Target Activity: Identification and Optimisation ofTrypanosoma bruceiGSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma bruceiDrug Discovery Lead Molecules (ChemMedChem 7/2013)

Author

Woodland, Andrew, primary, Grimaldi, Raffaella, additional, Luksch, Torsten, additional, Cleghorn, Laura A. T., additional, Ojo, Kayode K., additional, Van Voorhis, Wesley C., additional, Brenk, Ruth, additional, Frearson, Julie A., additional, Gilbert, Ian H., additional, and Wyatt, Paul G., additional

Published
2013
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16. From On-Target to Off-Target Activity: Identification and Optimisation ofTrypanosoma bruceiGSK3 Inhibitors and Their Characterisation as Anti-Trypanosoma bruceiDrug Discovery Lead Molecules

Author

Woodland, Andrew, primary, Grimaldi, Raffaella, additional, Luksch, Torsten, additional, Cleghorn, Laura A. T., additional, Ojo, Kayode K., additional, Van Voorhis, Wesley C., additional, Brenk, Ruth, additional, Frearson, Julie A., additional, Gilbert, Ian H., additional, and Wyatt, Paul G., additional

Published
2013
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17. Discovery of a Novel Class of Orally Active Trypanocidal N-Myristoyltransferase Inhibitors

Author

Brand, Stephen, primary, Cleghorn, Laura A. T., additional, McElroy, Stuart P., additional, Robinson, David A., additional, Smith, Victoria C., additional, Hallyburton, Irene, additional, Harrison, Justin R., additional, Norcross, Neil R., additional, Spinks, Daniel, additional, Bayliss, Tracy, additional, Norval, Suzanne, additional, Stojanovski, Laste, additional, Torrie, Leah S., additional, Frearson, Julie A., additional, Brenk, Ruth, additional, Fairlamb, Alan H., additional, Ferguson, Michael A. J., additional, Read, Kevin D., additional, Wyatt, Paul G., additional, and Gilbert, Ian H., additional

Published
2011
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18. Identification of Inhibitors of the Leishmania cdc2‐Related Protein Kinase CRK3

Author

Cleghorn, Laura A. T., primary, Woodland, Andrew, additional, Collie, Iain T., additional, Torrie, Leah S., additional, Norcross, Neil, additional, Luksch, Torsten, additional, Mpamhanga, Chido, additional, Walker, Roderick G., additional, Mottram, Jeremy C., additional, Brenk, Ruth, additional, Frearson, Julie A., additional, Gilbert, Ian H., additional, and Wyatt, Paul G., additional

Published
2011
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19. Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488

Author

Smith, Victoria C., primary, Cleghorn, Laura A. T., additional, Woodland, Andrew, additional, Spinks, Daniel, additional, Hallyburton, Irene, additional, Collie, Iain T., additional, Yi Mok, N., additional, Norval, Suzanne, additional, Brenk, Ruth, additional, Fairlamb, Alan H., additional, Frearson, Julie A., additional, Read, Kevin D., additional, Gilbert, Ian H., additional, and Wyatt, Paul G., additional

Published
2011
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28. Respiratory Flexibility in Response to Inhibition of Cytochrome cOxidase in Mycobacterium tuberculosis

Author

Arora, Kriti, Ochoa-Montaño, Bernardo, Tsang, Patricia S., Blundell, Tom L., Dawes, Stephanie S., Mizrahi, Valerie, Bayliss, Tracy, Mackenzie, Claire J., Cleghorn, Laura A. T., Ray, Peter C., Wyatt, Paul G., Uh, Eugene, Lee, Jinwoo, Barry, Clifton E., and Boshoff, Helena I.

Abstract

ABSTRACTWe report here a series of five chemically diverse scaffolds that have in vitroactivities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1complex in Mycobacterium tuberculosisin a strain-dependent manner. Deletion of the cytochrome bdoxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1complex and the risk of targeting energy metabolism with new drugs.

Published
2014
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31. Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

Author

Thomas MG, De Rycker M, Ajakane M, Albrecht S, Álvarez-Pedraglio AI, Boesche M, Brand S, Campbell L, Cantizani-Perez J, Cleghorn LAT, Copley RCB, Crouch SD, Daugan A, Drewes G, Ferrer S, Ghidelli-Disse S, Gonzalez S, Gresham SL, Hill AP, Hindley SJ, Lowe RM, MacKenzie CJ, MacLean L, Manthri S, Martin F, Miguel-Siles J, Nguyen VL, Norval S, Osuna-Cabello M, Woodland A, Patterson S, Pena I, Quesada-Campos MT, Reid IH, Revill C, Riley J, Ruiz-Gomez JR, Shishikura Y, Simeons FRC, Smith A, Smith VC, Spinks D, Stojanovski L, Thomas J, Thompson S, Underwood T, Gray DW, Fiandor JM, Gilbert IH, Wyatt PG, Read KD, and Miles TJ

Subjects
Animals, Female, Hep G2 Cells, Humans, Leishmania donovani drug effects, Male, Mice, Inbred BALB C, Molecular Structure, Morpholines chemical synthesis, Morpholines toxicity, Parasitic Sensitivity Tests, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors toxicity, Pyrazoles chemical synthesis, Pyrazoles toxicity, Pyrimidines chemical synthesis, Pyrimidines toxicity, Rats, Sprague-Dawley, Structure-Activity Relationship, Trypanocidal Agents chemical synthesis, Trypanocidal Agents toxicity, Leishmaniasis, Visceral drug therapy, Morpholines therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Trypanocidal Agents therapeutic use
Abstract

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

Published
2019
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32. Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

Author

Park Y, Pacitto A, Bayliss T, Cleghorn LA, Wang Z, Hartman T, Arora K, Ioerger TR, Sacchettini J, Rizzi M, Donini S, Blundell TL, Ascher DB, Rhee K, Breda A, Zhou N, Dartois V, Jonnala SR, Via LE, Mizrahi V, Epemolu O, Stojanovski L, Simeons F, Osuna-Cabello M, Ellis L, MacKenzie CJ, Smith AR, Davis SH, Murugesan D, Buchanan KI, Turner PA, Huggett M, Zuccotto F, Rebollo-Lopez MJ, Lafuente-Monasterio MJ, Sanz O, Diaz GS, Lelièvre J, Ballell L, Selenski C, Axtman M, Ghidelli-Disse S, Pflaumer H, Bösche M, Drewes G, Freiberg GM, Kurnick MD, Srikumaran M, Kempf DJ, Green SR, Ray PC, Read K, Wyatt P, Barry CE 3rd, and Boshoff HI

Subjects
Animals, Drug Design, Drug Discovery, Drug Resistance, Bacterial, Gene Expression Regulation, Bacterial drug effects, Gene Expression Regulation, Enzymologic drug effects, Humans, Mice, Mice, Inbred C57BL, Molecular Structure, Mutation, Protein Conformation, Rabbits, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Tuberculosis drug therapy, Antitubercular Agents pharmacology, IMP Dehydrogenase antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Sulfonamides pharmacology
Abstract

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

Published
2017
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33. Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.

Author

Brand S, Cleghorn LA, McElroy SP, Robinson DA, Smith VC, Hallyburton I, Harrison JR, Norcross NR, Spinks D, Bayliss T, Norval S, Stojanovski L, Torrie LS, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Read KD, Wyatt PG, and Gilbert IH

Subjects
Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Cell Line, Cell Survival drug effects, Crystallography, X-Ray, Databases, Factual, Humans, Models, Molecular, Molecular Conformation, Parasitic Sensitivity Tests, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides pharmacology, Trypanocidal Agents pharmacokinetics, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosomiasis, African drug therapy, Acyltransferases antagonists & inhibitors, Aminopyridines chemical synthesis, Sulfonamides chemical synthesis, Trypanocidal Agents chemical synthesis
Abstract

N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.

Published
2012
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