Open AccessSynthesis and Structure–Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens
Author(s) -
Bin Wu,
Xiaojian Yang,
Mingdi Yan
Publication year - 2019
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b00550
Subject(s) - auranofin , antimicrobial , chemistry , bacteria , thiol , microbiology and biotechnology , gram negative bacteria , gram positive bacteria , stereochemistry , biochemistry , escherichia coli , biology , organic chemistry , immunology , rheumatoid arthritis , genetics , gene
Auranofin, an FDA-approved arthritis drug, has recently been repurposed as a potential antimicrobial agent; it performed well against many Gram-positive bacteria, including multidrug resistant strains. It is, however, inactive toward Gram-negative bacteria, for which we are in dire need of new therapies. In this work, 40 auranofin analogues were synthesized by varying the structures of the thiol and phosphine ligands, and their activities were tested against ESKAPE pathogens. The study identified compounds that exhibited bacterial inhibition (MIC) and killing (MBC) activities up to 65 folds higher than that of auranofin, making them effective against Gram-negative pathogens. Both thiol and the phosphine structures influence the activities of the analogues. The trimethylphosphine and triethylphosphine ligands gave the highest activities against Gram-negative and Gram-positive bacteria, respectively. Our SAR study revealed that the thiol ligand is also very important, the structure of which can modulate the activities of the Au I complexes for both Gram-negative and Gram-positive bacteria. Moreover, these analogues had mammalian cell toxicities either similar to or lower than that of auranofin.