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

• Published in: Journal of medicinal chemistry Vol. 61; no. 16; pp. 7345 - 7357
• Main Authors: Abdeen, Sanofar, Kunkle, Trent, Salim, Nilshad, Ray, Anne-Marie, Mammadova, Najiba, Summers, Corey, Stevens, Mckayla, Ambrose, Andrew J., Park, Yangshin, Schultz, Peter G., Horwich, Arthur L., Hoang, Quyen Q., Chapman, Eli, Johnson, Steven M.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.08.2018; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - antagonists & inhibitors; Calorimetry - methods; Cell Line; Cell Survival - drug effects; Chaperonin 10 - antagonists & inhibitors; Chaperonin 10 - chemistry; Chaperonin 10 - metabolism; Chaperonin 60 - antagonists & inhibitors; Chemistry, Medicinal; Drug Evaluation, Preclinical - methods; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Humans; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemistry; Thiophenes - chemistry; CHAPERONIN GROEL; PROTEIN; TRANSTHYRETIN AMYLOIDOGENESIS INHIBITORS; SUBSTRUCTURE COMMON; OPTIMIZATION; ESKAPE PATHOGENS; ANTIMICROBIAL RESISTANCE; BINDING; DISCOVERY
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00989

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).