6533b858fe1ef96bd12b5b27

RESEARCH PRODUCT

Development of rhodesain inhibitors with a 3-bromoisoxazoline warhead

Roberta EttariLucia TamboriniPaola ContiIlenia C. AngeloSilvana GrassoLeonardo Lo PrestiCarlo De MicheliTanja SchirmeisterAndrea Pinto

subject

ProteasesStereochemistryPeptidomimeticCathepsin LMolecular ConformationStereoisomerismCysteine Proteinase InhibitorsBiologyCrystallography X-RayBiochemistryCysteine Proteinase InhibitorsCathepsin BCathepsin LinhibitorsDrug DiscoveryHumansMoietyGeneral Pharmacology Toxicology and PharmaceuticstrypanosomarhodesainPharmacologychemistry.chemical_classificationOrganic ChemistryStereoisomerismIsoxazolesisoxazolinesCombinatorial chemistryIn vitroCysteine EndopeptidasesEnzymechemistrypeptidomimeticsbiology.proteinMolecular Medicineinhibitors; isoxazolines; peptidomimetics; rhodesain; trypanosomaProtein Binding

description

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.

yearjournalcountryeditionlanguage
2013-01-01
http://hdl.handle.net/11570/3048174