Playing with opening and closing of heterocycles: Using the cusmano-ruccia reaction to develop a novel class of oxadiazolothiazinones, active as calcium channel modulators and P-glycoprotein inhibitors

Domenico Spinelli, Roberta Budriesi, Barbara Cosimelli, Elda Severi, Matteo Micucci, Massimo Baroni, Fabio Fusi, Pierfranco Ioan, Simon Cross, Maria Frosini, Simona Saponara, Rosanna Matucci, Camillo Rosano, Maurizio Viale, Alberto Chiarini, Emanuele Carosati

Research output: Contribution to journalArticle

Abstract

As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions.

Original languageEnglish
Pages (from-to)16543-16572
Number of pages30
JournalMolecules
Volume19
Issue number10
DOIs
Publication statusPublished - Oct 1 2014

Keywords

  • 3D-QSAR
  • Docking
  • Fingerprints for ligands and proteins (FLAP)
  • L-type calcium channels (LTCC)
  • Multidrug resistance (MDR1)
  • Negative inotropic activity
  • Oxadiazolothiazinones
  • Pharmacophore modeling
  • Ternary complex

ASJC Scopus subject areas

  • Organic Chemistry
  • Medicine(all)

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  • Cite this

    Spinelli, D., Budriesi, R., Cosimelli, B., Severi, E., Micucci, M., Baroni, M., Fusi, F., Ioan, P., Cross, S., Frosini, M., Saponara, S., Matucci, R., Rosano, C., Viale, M., Chiarini, A., & Carosati, E. (2014). Playing with opening and closing of heterocycles: Using the cusmano-ruccia reaction to develop a novel class of oxadiazolothiazinones, active as calcium channel modulators and P-glycoprotein inhibitors. Molecules, 19(10), 16543-16572. https://doi.org/10.3390/molecules191016543