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Molecules 2014, 19(10), 16543-16572; doi:10.3390/molecules191016543

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

1
Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum-Università di Bologna, Via F. Selmi 2, Bologna 40126, Italy
2
Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, Bologna 40126, Italy
3
Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, Napoli 80131, Italy
4
Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex HA5 5NE, UK
5
Dipartimento di Scienze della Vita, Università degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy
6
Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA) Viale Pieraccini 6, Firenze 50139, Italy
7
IRCCS Azienda Ospedaliera Universitaria San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, U.O.S. Biopolimeri e Proteomica, L.go R. Benzi, 10, Genova 16132, Italy
8
IRCCS Azienda Ospedaliera Universitaria San Martino—IST Istituto Nazionale per la Ricerca sul Cancro, U.O.C. Bioterapie, L.go R. Benzi, 10, Genova 16132, Italy
9
Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 10, Perugia 06123, Italy
*
Authors to whom correspondence should be addressed.
Received: 20 June 2014 / Revised: 15 August 2014 / Accepted: 4 September 2014 / Published: 14 October 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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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. View Full-Text
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 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
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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. 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 2014, 19, 16543-16572.

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