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
| Autor: | Simona Saponara, Massimo Baroni, Domenico Spinelli, Barbara Cosimelli, Elda Severi, Pierfranco Ioan, Camillo Rosano, Roberta Budriesi, Fabio Fusi, Rosanna Matucci, Emanuele Carosati, Simon Cross, Maria Frosini, Maurizio Viale, Alberto Chiarini, Matteo Micucci |
|---|---|
| Přispěvatelé: | 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., Domenico, Spinelli, Roberta, Budriesi, Cosimelli, Barbara, Elda, Severi, Matteo, Micucci, Massimo, Baroni, Fabio, Fusi, Pierfranco, Ioan, Simon, Cro, Maria, Frosini, Simona, Saponara, Rosanna, Matucci, Camillo, Rosano, Maurizio, Viale, Alberto, Chiarini, Emanuele, Carosati |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
oxadiazolothiazinones
Pharmaceutical Science Quantitative Structure-Activity Relationship Multidrug resistance ternary complex Analytical Chemistry Heterocyclic Compounds Drug Discovery Ternary complex L-type calcium channel Oxadiazoles Chemistry Calcium Channel Blockers Molecular Docking Simulation Subfamily B Chemistry (miscellaneous) docking Molecular Medicine ATP Binding Cassette Transporter Subfamily B Animals Guinea Pigs Heart Atria Muscle Smooth Structural Homology Protein Muscle Smooth Pharmacophore structure-activity relationship L-type calcium channels oxadiazolothiazinone P-glycoprotein Quantitative structure–activity relationship Stereochemistry In silico negative inotropic activity ATP Binding Cassette Transporter Fingerprints for Ligands and Proteins (FLAP) L-Type Calcium Channels (LTCC) Article lcsh:QD241-441 lcsh:Organic chemistry Homology modeling Physical and Theoretical Chemistry multidrug resistance (MDR1) 3D-QSAR Structural Homology Virtual screening Calcium channel Protein Organic Chemistry Combinatorial chemistry Docking (molecular) pharmacophore modeling |
| Zdroj: | Molecules, Vol 19, Iss 10, Pp 16543-16572 (2014) Molecules Volume 19 Issue 10 Pages 16543-16572 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|