title: Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones.
abstract: Oxadiazolo[3,4-c][1,4]thiazin-3-ones are cardiovascular agents that block L-type calcium channels. Previous data of cardiac and vasorelaxant activity on guinea-pig for several derivatives indicated the two positions ortho to the thiazine's sulphur as crucial for modulating the activity; but these positions are likely susceptible to metabolic biotransformations, as indicated by in silico predictions. We designed new derivatives, and obtained three negative inotropic agents with EC50 in the low nanomolar range, more potent than all the precursors published so far. In particular, benzocondensation at the thiazine ring led to 3a (EC50 = 0.013 μM) and 3b (EC50 = 0.006 μM). Besides negative inotropy, we also observed relaxant activity on nonvascular muscle in the micromolar range. We resolved the new derivatives by chiral chromatography, and determined their absolute configuration by comparing experimental and calculated chiroptical properties (VCD, ECD and ORD): they hold the same absolute configuration-optical rotation relationship, (S)-(+)/(R)-(-). Both cardiac and nonvascular activity are majorly or mostly retained in the R-form for all the compounds, but for the nonvascular activity we observed a strong stereoselectivity for 3a, with the R-form in the nanomolar range (IC50 = 0.020 μM) and 259-fold more potent than the S-one.
authors.affiliation: Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia, Via Elce di Sotto 10, 06123 Perugia, Italy. Electronic address: emanuele@chemiome.chm.unipg.it.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Carosati
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Ioan
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Barrano
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Caccamese
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy. Electronic address: barbara.cosimelli@unina.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Devlin
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.affiliation: Dipartimento di Chimica "G. Ciamician", Alma Mater Studiorum-Università di Bologna, Via Selmi 2, 40126 Bologna, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
authors.affiliation: Dipartimento di Scienze, Università della Basilicata, Viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Superchi
authors.affiliation: Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Budriesi
mesh_terms: D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010069:Oxadiazoles; D013843:Thiazines
keywords: Absolute configuration; Chiroptical spectroscopies; Circular dichroism; MetaSite; Negative inotropic activity; Pharmacological enantioselectivity