title: Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide.
abstract: Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound.
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Marina Maria
authors.initials: MM
authors.lastname: Carrozzo
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Umberto Maria
authors.initials: UM
authors.lastname: Battisti
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy. Electronic address: giuseppe.cannazza@unimore.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cannazza
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Puia
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ravazzini
authors.affiliation: Institute of Crystallography, CNR, Via Giovanni Amendola, 122/O, 70126 Bari, Italy.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Falchicchio
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Perrone
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Citti
authors.affiliation: Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Medical University of Lublin, ul. W. Chodzki 4a, 20-093 Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Braghiroli
authors.affiliation: Department of Life Sciences, University of Modena & Reggio Emilia, via Campi 287, 41125 Modena, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Parenti
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.
authors.forename: Luigino
authors.initials: L
authors.lastname: Troisi
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D018091:Receptors, AMPA / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000596440:7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo(e)pyrrolo(2,1-c)(1,2,4)thiadiazine 5,5-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D018091:Receptors, AMPA
keywords: AMPAr; Chiral benzothiadiazines; Cognitive enhancers; Enantiomerization; Stopped-flow chromatography