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.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano (Italy). roberta.ettari@unimi.it.
Roberta
R
Ettari
Lucia
L
Tamborini
Ilenia C
IC
Angelo
Silvana
S
Grasso
Tanja
T
Schirmeister
Leonardo
L
Lo Presti
Carlo
C
De Micheli
Andrea
A
Pinto
Paola
P
Conti
D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D057786:Peptidomimetics; D011485:Protein Binding; D013237:Stereoisomerism; D014345:Trypanosoma / Q000201:enzymology
D015853:Cysteine Proteinase Inhibitors; D007555:Isoxazoles; D057786:Peptidomimetics; D003546:Cysteine Endopeptidases; C446033:rhodesain; D002401:Cathepsin B; D056668:Cathepsin L
inhibitors; isoxazolines; peptidomimetics; rhodesain; trypanosoma