Development of Rhodesain Inhibitors with a 3‐Bromoisoxazoline Warhead

• DOI: 10.1002/cmdc.201300390
• Publication Date: 2013-11-15T13:31:04Z
• Authors: Roberta Ettari; Lucia Tamborini; Ilenia C. Angelo; Silvana Grasso; Tanja Schirmeister; Leonardo Lo Presti; Carlo De Micheli; Andrea Pinto; Paola Conti
• Keywords: 0301 basic medicine; Trypanosoma; Cathepsin L; Molecular Conformation; Stereoisomerism; Isoxazoles; Cysteine Proteinase Inhibitors; Crystallography, X-Ray; Cathepsin B; Cysteine Endopeptidases; 03 medical and health sciences; inhibitors ; isoxazolines ; peptidomimetics ; rhodesain ; trypanosoma; Humans; Peptidomimetics; inhibitors; isoxazolines; peptidomimetics; rhodesain; trypanosoma; Protein Binding

AbstractNovel 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.