Development of Rhodesain Inhibitors with a 3-Bromoisoxazoline Warhead

Novel rhodesain inhibitors were obtained by combining an enantiomerically pure 3-bromoisoxazoline warhead with a specific peptidomimetic recognition moiety. All derivatives behaved as inhibitors of rhodesain, with low micromolar Ki values. Their activity against the enzyme was found to be paralleled by an in vitro antitrypanosomal activity, with IC50 values in the mid-micromolar range. Notably, a preference for parasitic over human proteases, specifically cathepsins B and L, was observed. Awakened by the warhead: Novel rhodesain inhibitors with antitrypanosomal activity were developed by coupling a 3-bromoisoxazoline warhead to a suitable peptidomimetic recognition moiety.