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.
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.
authors.affiliation: Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum-Università di Bologna, Via F. Selmi 2, Bologna 40126, Italy. domenico.spinelli@unibo.it.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, Bologna 40126, Italy. roberta.budriesi@unibo.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, Napoli 80131, Italy. barbara.cosimelli@unina.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, Napoli 80131, Italy. elda.severi@unina.it.
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, Bologna 40126, Italy. matteo.micucci2@unibo.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Micucci
authors.affiliation: Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex HA5 5NE, UK. massimo@moldiscovery.com.
authors.forename: Massimo
authors.initials: M
authors.lastname: Baroni
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy. fabio.fusi@unisi.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, Bologna 40126, Italy. pierfranco.ioan3@unibo.it.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.affiliation: Molecular Discovery Ltd., 215 Marsh Road, Pinner, Middlesex HA5 5NE, UK. simon@moldiscovery.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Cross
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy. maria.frosini@unisi.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.affiliation: Dipartimento di Scienze della Vita, Università degli Studi di Siena, Via A. Moro 2, Siena 53100, Italy. simona.saponara@unisi.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
authors.affiliation: Dipartimento di Neuroscienze, Area del Farmaco e Salute del Bambino (NEUROFARBA) Viale Pieraccini 6, Firenze 50139, Italy. rosanna.matucci@unifi.it.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Matucci
authors.affiliation: 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. camillo.rosano@istge.it.
authors.forename: Camillo
authors.initials: C
authors.lastname: Rosano
authors.affiliation: 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. maurizio.viale@istge.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Viale
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, Bologna 40126, Italy. alberto.chiarini@unibo.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarini
authors.affiliation: Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 10, Perugia 06123, Italy. emanuele@chemiome.chm.unipg.it.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry*; D062105:Molecular Docking Simulation; D009130:Muscle, Smooth / Q000187:drug effects; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D040681:Structural Homology, Protein
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D002121:Calcium Channel Blockers; D006571:Heterocyclic Compounds; D010069:Oxadiazoles