title: Synthesis and biological evaluation of papain-family cathepsin L-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antiprotozoal agents.
abstract: Novel papain-family cathepsin L-like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure-activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3-bromoisoxazoline moiety. Several rhodesain and falcipain-2 inhibitors displaying single-digit micromolar or sub-micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, 20133 Milano (Italy). roberta.ettari@unimi.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ettari
authors.forename: Andrea
authors.initials: A
authors.lastname: Pinto
authors.forename: Lucia
authors.initials: L
authors.lastname: Tamborini
authors.forename: Ilenia C
authors.initials: IC
authors.lastname: Angelo
authors.forename: Silvana
authors.initials: S
authors.lastname: Grasso
authors.forename: Maria
authors.initials: M
authors.lastname: Zappalà
authors.forename: Natale
authors.initials: N
authors.lastname: Capodicasa
authors.forename: Laura
authors.initials: L
authors.lastname: Yzeiraj
authors.forename: Esther
authors.initials: E
authors.lastname: Gruber
authors.forename: Makoah N
authors.initials: MN
authors.lastname: Aminake
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Tanja
authors.initials: T
authors.lastname: Schirmeister
authors.forename: Carlo
authors.initials: C
authors.lastname: De Micheli
authors.forename: Paola
authors.initials: P
authors.lastname: Conti
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014345:Trypanosoma / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents; D015853:Cysteine Proteinase Inhibitors; D001569:Benzodiazepines; D003546:Cysteine Endopeptidases; C446033:rhodesain; D002401:Cathepsin B; D056668:Cathepsin L
keywords: antiprotozoal agents; inhibitors; malaria; peptidomimetics; structure-activity relationships