Structural investigations on the mitochondrial uncouplers niclosamide and FCCP

Abstract

There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p‐(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure–activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4′‐nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development.

The Antifungal Potential of Niclosamide and Structurally Related Salicylanilides

“…Fluorine substituents were less tolerated in tests with Candida albicans [ 51 ]. Although the absence of the para -nitro group retained the inhibition of oxidative phosphorylation, a more recent study disclosed a distinctly reduced activity of the niclosamide analog lacking the para -nitro substituent [ 39 , 101 ]. Bulky para -substituents were also tolerated in active salicylanilides such as rafoxanide.…”