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

Ottavi, Samantha; Scarry, Sarah M.; Mosior, John; Ling, Yan; Roberts, Julia; Singh, Amrita; Zhang, David; Goullieux, Laurent; Roubert, Christine; Bacqué, Eric; Lagiakos, H. Rachel; Vendome, Jeremie; Moraca, Francesca; Li, Kelin; Perkowski, Andrew J.; Ramesh, Remya; Bowler, Matthew M.; Tracy, William; Feher, Victoria A.; Sacchettini, James C.; Gold, Ben S.; Nathan, Carl F.; Aubé, Jeffrey

doi:10.1021/acs.jmedchem.1c01565

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

Journal Article · 18 January 2022 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.1c01565 · OSTI ID:1845485

Ottavi, Samantha ^[1]; Scarry, Sarah M. ^[1]; Mosior, John ^[2]; Ling, Yan ^[3]; Roberts, Julia ^[3]; Singh, Amrita ^[3]; Zhang, David ^[3]; Goullieux, Laurent ^[4]; Roubert, Christine ^[4]; Bacqué, Eric ^[4]; Lagiakos, H. Rachel ^[5]; Vendome, Jeremie ^[5];

^[5]; Li, Kelin ^[1]; Perkowski, Andrew J. ^[1]; Ramesh, Remya ^[1]; Bowler, Matthew M. ^[1]; Tracy, William ^[1]; Feher, Victoria A. ^[5];

^[2] more »

Univ. of North Carolina, Chapel Hill, NC (United States)
Texas Agricultural and Mechanical Univ., College Station, TX (United States)
Cornell Univ., Ithaca, NY (United States). Weill Medical College
Evotec ID (Lyon) (France)
Schrödinger, Inc., New York, NY (United States)

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_v1.2 and Na_v1.5 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).

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1845485

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 3 Vol. 65; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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