Rhodesain inhibitors on the edge of reversibility-irreversibility

A comparative study of Michael acceptor and keto-Michael acceptor inhibitors of the cysteine protease rhodesain has been performed. Five new inhibitors have been prepared bearing the peptide structure of the known cysteine protease inhibitor K11777 and differing on the warhead. For the preparation of the Michael acceptor warhead, a Horner-Wadsworth-Emmons reaction was used. In the synthetic routes of the keto-Michael acceptor warheads, keto-enoate and keto-vinyl sulfone, a metathesis reaction and a radical sulfonylation were the key steps, respectively. Interestingly, keto-Michael acceptors inhibited rhodesain through a dual mode of action, showing reversibility at low inhibitor concentrations and irreversibility at high inhibitor concentrations.