192565-82-5Relevant academic research and scientific papers
Repurposing the antihistamine terfenadine for antimicrobial activity against staphylococcus aureus
Perlmutter, Jessamyn I.,Forbes, Lauren T.,Krysan, Damian J.,Ebsworth-Mojica, Katherine,Colquhoun, Jennifer M.,Wang, Jenna L.,Dunman, Paul M.,Flaherty, Daniel P.
, p. 8540 - 8562 (2014)
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.
Structural determinants for histamine H1 affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs
Aslanian, Robert,Piwinski, John J.,Zhu, Xiaohong,Priestley, Tony,Sorota, Steve,Du, Xiao-Yi,Zhang, Xue-Song,McLeod, Robbie L.,West, Robert E.,Williams, Shirley M.,Hey, John A.
supporting information; experimental part, p. 5043 - 5047 (2010/03/31)
In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H1 binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H1 assays.
