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NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

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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.

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Acknowledgments

We gratefully thank the MIUR (Ministero dell’Istruzione, Università e Ricerca) for supporting our research.

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Authors and Affiliations

  1. Department of Chemical Sciences, University of Messina, via D’Alcontres 31, 98166, Messina, Italy

    Archimede Rotondo & Silvana Grasso

  2. Department of Drug Sciences and Products for Health, University of Messina, Viale Annunziata, 98168, Messina, Italy

    Roberta Ettari & Maria Zappalà

Authors
  1. Archimede Rotondo
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  2. Roberta Ettari
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  3. Silvana Grasso
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  4. Maria Zappalà
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Correspondence to Archimede Rotondo.

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Rotondo, A., Ettari, R., Grasso, S. et al. NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors. Struct Chem 26, 943–950 (2015). https://doi.org/10.1007/s11224-015-0597-5

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