posted on 2022-01-28, 18:06authored byDavid Cisneros, Eduardo J. Cueto-Díaz, Tania Medina-Gil, Rebecca Chevillard, Teresa Bernal-Fraile, Ramón López-Sastre, Mustafa M. Aldfer, Marzuq A. Ungogo, Hamza A. A. Elati, Natsumi Arai, Momoka Otani, Shun Matsushiro, Chiaki Kojima, Godwin U. Ebiloma, Tomoo Shiba, Harry P. de Koning, Christophe Dardonville
The trypanosome alternative
oxidase (TAO), a mitochondrial enzyme
involved in the respiration of the bloodstream form trypomastigotes
of Trypanosoma brucei, is a validated
drug target against African trypanosomes. Earlier series of TAO inhibitors
having a 2,4-dihydroxy-6-methylbenzoic acid scaffold (“head”)
and a triphenylphosphonium or quinolin-1-ium cation as a mitochondrion-targeting
group (“tail”) were shown to be nanomolar inhibitors
in enzymatic and cellular assays. We investigated here the effect
of different mitochondrion-targeting cations and other scaffold modifications
on the in vitro activity of this class of inhibitors. Low micromolar
range activities were obtained, and the structure–activity
relationship studies showed that modulation of the tail region with
polar substituents is generally detrimental to the enzymatic and cellular
activity of TAO inhibitors.