In Vitro and In Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas.

Autor: Ottavi S; 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., Scarry SM; 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., Mosior J; Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas 77843, United States., Ling Y; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States., Roberts J; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States., Singh A; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States., Zhang D; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States., Goullieux L; Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, Lyon 69001, France., Roubert C; Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, Lyon 69001, France., Bacqué E; Evotec ID (Lyon), SAS 40 Avenue Tony Garnier, Lyon 69001, France., Lagiakos HR; Schrödinger, Inc., 120 W. 45 Street, New York, New York 10036, United States., Vendome J; Schrödinger, Inc., 120 W. 45 Street, New York, New York 10036, United States., Moraca F; Schrödinger, Inc., 120 W. 45 Street, New York, New York 10036, United States., Li K; 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., Perkowski AJ; 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., Ramesh R; 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., Bowler MM; 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., Tracy W; 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., Feher VA; Schrödinger, Inc., 120 W. 45 Street, New York, New York 10036, United States., Sacchettini JC; Departments of Biochemistry and Biophysics, Texas Agricultural and Mechanical University, College Station, Texas 77843, United States., Gold BS; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States., Nathan CF; Department of Microbiology & Immunology, Weill Cornell Medicine, New York, New York 10065, United States.; Department of Medicine, Weill Cornell Medicine, New York, New York 10065, United States., Aubé J; 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.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 1996-2022. Date of Electronic Publication: 2022 Jan 19.
DOI: 10.1021/acs.jmedchem.1c01565
Abstrakt: A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis . The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 ( 1 ), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1 , have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Ca v 1.2 and Na v 1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k ( p -benzamide) and 5n ( p -phenylsulfonamide).
Databáze: MEDLINE
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