Synthesis and biological evaluation of papain-family cathepsinl-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antiprotozoal agents
Articolo
Data di Pubblicazione:
2014
Citazione:
Synthesis and biological evaluation of papain-family cathepsinl-like cysteine protease inhibitors containing a 1,4-benzodiazepine scaffold as antiprotozoal agents / R. Ettari, A. Pinto, L. Tamborini, I.C. Angelo, S. Grasso, M. Zappalà, N. Capodicasa, L. Yzeiraj, E. Gruber, M.N. Aminake, G. Pradel, T. Schirmeister, C. De Micheli, P. Conti. - In: CHEMMEDCHEM. - ISSN 1860-7179. - 9:8(2014 Aug), pp. 1817-1825. [10.1002/cmdc.201402079]
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
antiprotozoal agents; inhibitors; malaria; peptidomimetics; structure-activity relationships
Elenco autori:
R. Ettari, A. Pinto, L. Tamborini, I.C. Angelo, S. Grasso, M. Zappalà, N. Capodicasa, L. Yzeiraj, E. Gruber, M.N. Aminake, G. Pradel, T. Schirmeister, C. De Micheli, P. Conti
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