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J Med Chem. 2014 Oct 23;57(20):8540-62. doi: 10.1021/jm5010682. Epub 2014 Oct 6.

Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus.

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Department of Microbiology and Immunology, University of Rochester Medical Center , 601 Elmwood Avenue, Rochester, New York 14642, United States.


Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.

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