91065-26-8Relevant academic research and scientific papers
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
Spinelli, Domenico,Budriesi, Roberta,Cosimelli, Barbara,Severi, Elda,Micucci, Matteo,Baroni, Massimo,Fusi, Fabio,Ioan, Pierfranco,Cross, Simon,Frosini, Maria,Saponara, Simona,Matucci, Rosanna,Rosano, Camillo,Viale, Maurizio,Chiarini, Alberto,Carosati, Emanuele
, p. 16543 - 16572 (2014)
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. Copyright:
