Synthesis and Structure-Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens.

Journal of Medicinal Chemistry
Bin WuMingdi Yan

Abstract

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 AuI 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.

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Citations

Mar 4, 2020·International Journal of Oncology·Romina Gabriela ArmandoDaniel Eduardo Gomez
Feb 27, 2021·Bioorganic & Medicinal Chemistry Letters·Mathieu MichautGaëtan L A Mislin
Mar 17, 2020·Bioorganic & Medicinal Chemistry Letters·Mathieu MichautGaëtan L A Mislin
May 8, 2021·Journal of Medical Microbiology·Andris Evans, Kevin A Kavanagh
Jul 19, 2021·European Journal of Medicinal Chemistry·Jing LiangLixia Chen
Aug 6, 2021·Advanced Healthcare Materials·William NdugireMingdi Yan
Sep 6, 2019·ACS Infectious Diseases·Tessa D EpsteinDanielle H Dube

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