Sleeping sickness or human African trypanosomiasis (HAT), is a vector-borne parasitic disease. It is caused by infection with protozoan parasites belonging to the genus Trypanosoma (T. brucei sp.). Without treatment, the disease is usually fatal.

Our research of a novel and effective chemotherapy of HAT is based on the inhibition of the Trypanosome Alternative Oxidase (TAO). TAO is essential for the respiration of bloodstream form trypomastigotes because it is the only enzyme available to re-oxidize the NADH produced during glycolysis. This enzyme, which is conserved among trypanosome subspecies and has no counterpart in mammalian cells, is a validated drug target against trypanosomes.

In previous studies, the structure – activity relationships (SAR) of different TAO inhibitors derived from 4-hydroxybenzoate and 4-alkoxybenzaldehyde was investigated. These compounds were shown to exhibit TAO inhibitory activity at the nanomolar level, showing trypanocidal activity in in vitro and in vivo assays.

In the current study, new analogs have been synthesized with the aim of extending the SAR studies of TAO inhibitors. In this case, the ester bond has been replaced by an amide bond, which is more metabolically stable. In addition, new cationic groups such as benzamidinium, 2-phenylimidazolin-3-ium and 2- (phenylamino) imidazolin-3-ium cations have been incorporated.

We gratefully acknowledge Ministerio de Ciencia, Innovación y Universidades (project RTI2018-093940-B-I00), for financial support.