Identification of constrained peptidomimetics carrying a Michael acceptor warhead as antitrypanosomal agents

In this structure-activity relationship (SAR) study, we report the development of rhodesain-targeting peptidomimetics with antitrypanosomal activity. The new compounds (SPR65-SPR80) feature the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) moiety as conformationally constrained Phe analog. Various substituents were inserted at the P1 and P3 positions, and the methyl vinyl ketone moiety was introduced as warhead. The incorporation of Tic resulted in reduced affinity against rhodesain compared to the parent compounds containing Phe (2a-m), suggesting that its rigidity negatively affects target binding. Nevertheless, promising EC₅₀ values ranging from 0.42 to 1.35 μM were observed in cell-based assays, probably due to better pharmacokinetic properties and/or interactions with additional protozoal targets. CC₅₀ values > 100 μM were observed. Therefore, while Tic is less tolerated by rhodesain, its incorporation in peptidomimetic Michael acceptors led to antitrypanosomal effects that were comparable or slightly better than those of the parent compounds and no cytotoxicity up to 100 μM. These findings could be taken into consideration in future SAR studies aimed at the development of antitrypanosomal agents.