Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis.

This paper describes an optimization strategy of the highly active vinyl ketone which was recognized as a strong inhibitor of rhodesain of , endowed with a value of 67 × 10 M min coupled with a high binding affinity ( = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e., vinyl ketones and . Vinyl ketone showed an impressive potency toward rhodesain ( = 8811 × 10) coupled to a good antiparasitic activity (EC = 3.6 μM), while vinyl ketone proved to possess the highest binding affinity toward the trypanosomal protease ( = 0.6 pM) and a submicromolar antiparasitic activity (EC = 0.67 μM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.