Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 9, Pages 3962-3983Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01903
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Funding
- University of Florida
- University of Florida Graduate School Fellowship
- National Science Foundation through the National High Magnetic Field Laboratory
- NIH [S10 OD021758-01A1]
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Bacterial biofilms are surface-attached communities comprised of nonreplicating persister cells housed within a protective extracellular matrix. Biofilms display tolerance toward conventional antibiotics, occur in similar to 80% of infections, and lead to >500000 deaths annually. We recently identified halogenated phenazine (HP) analogues which demonstrate biofilmeradicating activities against priority pathogens; however, the synthesis of phenazines presents limitations. Herein, we report a refined HP synthesis which expedited the identification of improved biofilm-eradicating agents. 1-Methoxyphenazine scaffolds were generated through a Buchwald Hartwig cross-coupling (70% average yield) and subsequent reductive cyclization (68% average yield), expediting the discovery of potent biofilm-eradicating HPs (e.g., 61: MRSA BAA-1707 MBEC = 4.69 mu M). We also developed bacterial-selective prodrugs (reductively activated quinone-alkyloxycarbonyloxymethyl moiety) to afford HP 87, which demonstrated excellent antibacterial and biofilm eradication activities against MRSA BAA-1707 (MIC = 0.15 mu M, MBEC = 12.5 mu M). Furthermore, active HPs herein exhibit negligible cytotoxic or hemolytic effects, highlighting their potential to target biofilms.
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