Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA)

Sanofar Abdeen, Trent Kunkle, Nilshad Salim, Anne Marie Ray, Najiba Mammadova, Corey Summers, McKayla Stevens, Andrew J. Ambrose, Yangshin Park, Peter G. Schultz, Arthur L. Horwich, Quyen Q. Hoang, Eli Chapman, Steven M. Johnson

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9 Scopus citations

Abstract

Extending from a study we recently published examining the antitrypanosomal effects of a series of GroEL/ES inhibitors based on a pseudosymmetrical bis-sulfonamido-2-phenylbenzoxazole scaffold, here, we report the antibiotic effects of asymmetric analogs of this scaffold against a panel of bacteria known as the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). While GroEL/ES inhibitors were largely ineffective against K. pneumoniae, A. baumannii, P. aeruginosa, and E. cloacae (Gram-negative bacteria), many analogs were potent inhibitors of E. faecium and S. aureus proliferation (Gram-positive bacteria, EC50 values of the most potent analogs were in the 1-2 μM range). Furthermore, even though some compounds inhibit human HSP60/10 biochemical functions in vitro (IC50 values in the 1-10 μM range), many of these exhibited moderate to low cytotoxicity to human liver and kidney cells (CC50 values > 20 μM).

Original languageEnglish (US)
Pages (from-to)7345-7357
Number of pages13
JournalJournal of Medicinal Chemistry
Volume61
Issue number16
DOIs
StatePublished - Aug 23 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Abdeen, S., Kunkle, T., Salim, N., Ray, A. M., Mammadova, N., Summers, C., Stevens, M., Ambrose, A. J., Park, Y., Schultz, P. G., Horwich, A. L., Hoang, Q. Q., Chapman, E., & Johnson, S. M. (2018). Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA). Journal of Medicinal Chemistry, 61(16), 7345-7357. https://doi.org/10.1021/acs.jmedchem.8b00989