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 3 which was recognized as a strong inhibitor
of rhodesain of Trypanosoma brucei rhodesiense, endowed
with a ksecond value of 67 × 106 M–1 min–1 coupled with
a high binding affinity (Ki = 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 4h and 4k. Vinyl ketone 4h showed
an impressive potency toward rhodesain (ksecond = 8811 × 105) coupled to a good antiparasitic activity
(EC50 = 3.6 μM), while vinyl ketone 4k proved to possess the highest binding affinity toward the trypanosomal
protease (Ki = 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.