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 EC