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Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents
Author(s) -
Ettari Roberta,
Pinto Andrea,
Tamborini Lucia,
Angelo Ilenia C.,
Grasso Silvana,
Zappalà Maria,
Capodicasa Natale,
Yzeiraj Laura,
Gruber Esther,
Aminake Makoah N.,
Pradel Gabriele,
Schirmeister Tanja,
De Micheli Carlo,
Conti Paola
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402079
Subject(s) - cysteine protease , papain , chemistry , cysteine proteinase inhibitors , moiety , cathepsin , stereochemistry , antiparasitic , cysteine , structure–activity relationship , cathepsin l , combinatorial chemistry , cathepsin k , antiprotozoal , protease , biochemistry , enzyme , in vitro , medicine , apoptosis , pathology , osteoclast , programmed cell death , caspase
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.