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
  • 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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