Trypanosoma cruzi, the causative agent of Chagas' disease, affects tens of millions of South Americans. One of the most studied T. cruzi-biomolecules as a target for drug development is cruzipain, an essential cysteine proteinase of this parasite. Some of our recent studies identified amidine containing benzofuroxans as hit compounds for cruzipain inhibition with trypanosomicidal activities. Experimental and theoretical studies inspired us to modify these compounds by maintaining the amidine motif and using benzofuroxan and benzimidazole 1,3-dioxide systems as core scaffolds in order to obtain better cruzipain inhibitors. The new amidines had excellent trypanosomicidal activity, with good selectivity indexes, but without improved cruzipain-inhibitory activities compared with the parent compounds. The interaction of amidines with cruzipain has been investigated through a combined NMR -T1-differences, DOSY, and STD- and molecular docking approaches. Despite the low cruzipain-inhibition ability, our data suggest that these designed compounds have relevant structural features, i.e. aromatic groups and protonated moieties with stabilizing complex ability using stacking and electrostatic interactions, respectively, that bind reversibly to cruzipain.