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

Abstract

This paper describes an optimization strategy of the highly active vinyl ketone <b>3</b> which was recognized as a strong inhibitor of rhodesain of <i>Trypanosoma brucei rhodesiense</i>, endowed with a <i>k</i>_second value of 67 × 10⁶ M^-1 min^-1 coupled with a high binding affinity (<i>K</i>_i = 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 <b>4h</b> and <b>4k</b>. Vinyl ketone <b>4h</b> showed an impressive potency toward rhodesain (<i>k</i>_second = 8811 × 10⁵) coupled to a good antiparasitic activity (EC₅₀ = 3.6 μM), while vinyl ketone <b>4k</b> proved to possess the highest binding affinity toward the trypanosomal protease (<i>K</i>_i = 0.6 pM) and a submicromolar antiparasitic activity (EC₅₀ = 0.67 μM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.