2. Academic Validation
  3. Mycobacterium tuberculosis PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas

Mycobacterium tuberculosis PptT Inhibitors Based on Heterocyclic Replacements of Amidinoureas

  • ACS Med Chem Lett. 2023 Jun 26;14(7):970-976. doi: 10.1021/acsmedchemlett.3c00162.
Samantha Ottavi 1,  Kelin Li 1,  Jackson G Cacioppo 2,  Andrew J Perkowski 1,  Remya Ramesh 1,  Ben S Gold 3,  Yan Ling 3,  Julia Roberts 3,  Amrita Singh 3,  David Zhang 3,  John Mosior 4,  Laurent Goullieux 5,  Christine Roubert 5,  Eric Bacqué 5,  James C Sacchettini 4,  Carl F Nathan 3,  Jeffrey Aubé 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry, UNC College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States.
  • 4 Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas 77843, United States.
  • 5 Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, 69001 Lyon, France.
PMID: 37465309 DOI: 10.1021/acsmedchemlett.3c00162
Abstract

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.

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