Novel aroyl guanidine anti-trypanosomal compounds that exert opposing effects on parasite energy metabolism

Human African trypanosomiasis (HAT), or sleeping sickness, is a neglected tropical disease with current treatments marred by severe side effects or delivery issues. To identify novel classes of compounds for the treatment of HAT, high throughput screening (HTS) had previously been conducted on bloodstream forms of T. b. brucei, a model organism closely related to the human pathogens T. b. gambiense and T. b. rhodesiense. This HTS had identified a number of structural classes with potent bioactivity against T. b. brucei (IC50 ≤ 10 μM) with selectivity over mammalian cell-lines (selectivity index of ≥10). One of the confirmed hits was an aroyl guanidine derivative. Deemed to be chemically tractable with attractive physicochemical properties, here we explore this class further to develop the SAR landscape. We also report the influence of the elucidated SAR on parasite metabolism, to gain insight into possible modes of action of this class. Of note, two sub-classes of analogues were identified that generated opposing metabolic responses involving disrupted energy metabolism. This knowledge may guide the future design of more potent inhibitors, while retaining the desirable physicochemical properties and an excellent selectivity profile of the current compound class. [Display omitted] •SAR exploration of the acyl guanidine hit 1 against T. b. brucei led to the discovery of 27 (IC50 0.75 μM).•Metabolomics analysis suggested that 18, 19, and 29 may be involved in the inhibition of parasite ATP consumption.•In stark contrast, metabolomics analysis suggested that 25, 34, 38 and 39 may direct an elevated parasite ATP consumption.•Opposing effects on the metabolic phenotype of ATP are hence observed in subclasses of the same antiparasitic chemotype.•Awareness of the potential of metabolic divergence is paramount when interpreting antiparasitic SAR.