{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T14:37:42Z","timestamp":1761489462506,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2014,10,14]],"date-time":"2014-10-14T00:00:00Z","timestamp":1413244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/molecules191016543","type":"journal-article","created":{"date-parts":[[2014,10,14]],"date-time":"2014-10-14T10:28:18Z","timestamp":1413282498000},"page":"16543-16572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["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"],"prefix":"10.3390","volume":"19","author":[{"given":"Domenico","family":"Spinelli","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica \"G. Ciamician\", Alma Mater Studiorum-Universit\u00e0 di Bologna, Via F. Selmi 2, Bologna 40126, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Budriesi","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Universit\u00e0 di Bologna, Via Belmeloro 6, Bologna 40126, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Cosimelli","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Universit\u00e0 di Napoli \"Federico II\", Via D. Montesano 49, Napoli 80131, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elda","family":"Severi","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia, Universit\u00e0 di Napoli \"Federico II\", Via D. Montesano 49, Napoli 80131, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Micucci","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Universit\u00e0 di Bologna, Via Belmeloro 6, Bologna 40126, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Baroni","sequence":"additional","affiliation":[{"name":"Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex HA5 5NE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Fusi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita, Universit\u00e0 degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierfranco","family":"Ioan","sequence":"additional","affiliation":[{"name":"Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Universit\u00e0 di Bologna, Via Belmeloro 6, Bologna 40126, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Cross","sequence":"additional","affiliation":[{"name":"Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex HA5 5NE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Frosini","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita, Universit\u00e0 degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3831-8669","authenticated-orcid":false,"given":"Simona","family":"Saponara","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita, Universit\u00e0 degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanna","family":"Matucci","sequence":"additional","affiliation":[{"name":"Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA) Viale Pieraccini 6, Firenze 50139, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camillo","family":"Rosano","sequence":"additional","affiliation":[{"name":"IRCCS Azienda Ospedaliera Universitaria San Martino\u2014IST Istituto Nazionale per la Ricerca sul Cancro, U.O.S. Biopolimeri e Proteomica, L.go R. 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