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Mycobacterium tuberculosis PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas

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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2023, 14, 7, 970-976
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    Mycobacterium tuberculosis PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas
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    • Samantha Ottavi
      Samantha Ottavi
      Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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      Orcidhttps://orcid.org/0000-0002-2238-7512
    • Kelin Li
      Kelin Li
      Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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    • Jackson G. Cacioppo
      Jackson G. Cacioppo
      Department of Chemistry, UNC College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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      Orcidhttps://orcid.org/0000-0002-6514-0739
    • Andrew J. Perkowski
      Andrew J. Perkowski
      Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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      Orcidhttps://orcid.org/0009-0000-1143-8962
    • Remya Ramesh
      Remya Ramesh
      Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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    • Ben S. Gold
      Ben S. Gold
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
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      Orcidhttps://orcid.org/0000-0002-9562-8241
    • Yan Ling
      Yan Ling
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
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    • Julia Roberts
      Julia Roberts
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
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    • Amrita Singh
      Amrita Singh
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
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      Orcidhttps://orcid.org/0000-0001-5649-8483
    • David Zhang
      David Zhang
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
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    • John Mosior
      John Mosior
      Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas 77843, United States
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    • Laurent Goullieux
      Laurent Goullieux
      Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, 69001 Lyon, France
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    • Christine Roubert
      Christine Roubert
      Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, 69001 Lyon, France
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    • Eric Bacqué
      Eric Bacqué
      Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, 69001 Lyon, France
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    • James C. Sacchettini
      James C. Sacchettini
      Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas 77843, United States
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      Orcidhttps://orcid.org/0000-0001-5767-2367
    • Carl F. Nathan*
      Carl F. Nathan
      Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States
      *Email: [email protected]
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    • Jeffrey Aubé*
      Jeffrey Aubé
      Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      Department of Chemistry, UNC College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-1049-5767
    Other Access OptionsSupporting Information (1)

    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2023, 14, 7, 970–976
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.3c00162
    Published June 26, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    4′-Phosphopantetheinyl transferase (PptT) is an essential enzyme for Mycobacterium tuberculosis (Mtb) survival and virulence and therefore an attractive target for a tuberculosis therapeutic. In this work, two modeling-informed approaches toward the isosteric replacement of the amidinourea moiety present in the previously reported PptT inhibitor AU 8918 are reported. Although a designed 3,5-diamino imidazole unexpectedly adopted an undesired tautomeric form and was inactive, replacement of the amidinourea moiety afforded a series of active PptT inhibitors containing 2,6-diaminopyridine scaffolds.

    Copyright © 2023 American Chemical Society

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    This article is cited by 5 publications.

    1. Terry W. Moore, (Editorial Advisory Board, ACS Medicinal Chemistry Letters)William C. K. Pomerantz (Topic Editor, ACS Medicinal Chemistry Letters). Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue. Journal of Medicinal Chemistry 2024, 67 (9) , 6895-6896. https://doi.org/10.1021/acs.jmedchem.4c00716
    2. Terry W. Moore, (Editorial Advisory Board, ACS Medicinal Chemistry Letters)William C. K. Pomerantz (Topic Editor, ACS Medicinal Chemistry Letters). Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue. ACS Medicinal Chemistry Letters 2024, 15 (5) , 565-566. https://doi.org/10.1021/acsmedchemlett.4c00139
    3. Beatriz M. Rocha, Eugénia Pinto, Emília Sousa, Diana I. S. P. Resende. Targeting Siderophore Biosynthesis to Thwart Microbial Growth. International Journal of Molecular Sciences 2025, 26 (8) , 3611. https://doi.org/10.3390/ijms26083611
    4. Amrita Singh, Samantha Ottavi, Inna Krieger, Kyle Planck, Andrew Perkowski, Takushi Kaneko, Andrew M. Davis, Christine Suh, David Zhang, Laurent Goullieux, Alexander Alex, Christine Roubert, Mark Gardner, Marian Preston, Dave M. Smith, Yan Ling, Julia Roberts, Bastien Cautain, Anna Upton, Christopher B. Cooper, Natalya Serbina, Zaid Tanvir, John Mosior, Ouathek Ouerfelli, Guangli Yang, Ben S. Gold, Kyu Y. Rhee, James C. Sacchettini, Nader Fotouhi, Jeffrey Aubé, Carl Nathan. Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase. Science Advances 2024, 10 (11) https://doi.org/10.1126/sciadv.adj6406
    5. Zhen-Xi Niu, Ya-Tao Wang, Jin-Feng Sun, Peng Nie, Piet Herdewijn. Recent advance of clinically approved small-molecule drugs for the treatment of myeloid leukemia. European Journal of Medicinal Chemistry 2023, 261 , 115827. https://doi.org/10.1016/j.ejmech.2023.115827
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    ACS Medicinal Chemistry Letters

    Cite this: ACS Med. Chem. Lett. 2023, 14, 7, 970–976
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsmedchemlett.3c00162
    Published June 26, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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