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.
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|Titolo:||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.|
|Citazione:||Spinelli, D., Budriesi, R., Cosimelli, B., Severi, E., Micucci, M., Baroni, M., et al. (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.|
|Appare nelle tipologie:||1.1 Articolo in rivista|