| Summary: | Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The development of molecules targeting rhodesain, the main cysteine protease of <i>T. b. rhodesiense</i>, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (<b>SPR10</b>–<b>SPR19</b>) as potential anti-HAT agents. The new molecules show <i>K</i><sub>i</sub> values in the low-micro/sub-micromolar range against rhodesain, coupled with <i>k</i><sub>2nd</sub> values between 1314 and 6950 M<sup>−1</sup> min<sup>−1</sup>. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against <i>T. b. brucei</i> cultures, <b>SPR16</b> and <b>SPR18</b> exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor <b>SPR34</b> highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents
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