328917-83-5Relevant academic research and scientific papers
NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors
Rotondo, Archimede,Ettari, Roberta,Grasso, Silvana,Zappalà, Maria
, p. 943 - 950 (2015/08/03)
Abstract Conformational analysis of a potent class of cysteine protease inhibitors is thoroughly studied by NMR, in both, polar and apolar solvents to get a better insight over the known biological activity and migration through biological media. These molecules are composed by a benzodiazepine (BDZ) scaffold connected to a bromo-isoxazoline (IOX) ring through an alkyl spacer (AS) with up to four-carbon atoms. Data, supported by theoretical calculations at DFT level, reveal that both BDZ and IOX keep a pretty rigid and asymmetric conformation, so that four diastereo-atropisomers (two mirror-image couples) are generated. The relative stiffness of these substrates, maintained also in different solvents, is confirmed by: (a) remarkable separation of diastereotopic protons; (b) specific through the space contacts (NOESY); and (c) very good fitting of the coupling constants evaluations. The prototypic compound with the longer AS shows two main conformations and a certain dynamic freedom around the AS torsional angles close to IOX; according to our data, the AS length is not fundamental for the functional BDZ and IOX fitting into the macromolecular complex; however, it does play a crucial role to cross the parasite cell membranes.
Synthesis and biological evaluation of papain-family cathepsin l-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antiprotozoal agents
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
, p. 1817 - 1825 (2014/08/18)
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.
