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.

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 / Carrozzo, Marina Maria; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Puja, Giulia; Ravazzini, Federica; Falchicchio, Aurelia; Perrone, Serena; Citti, Cinzia; Jozwiak, Krzysztof; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 22(2014), pp. 4667-4676. [10.1016/j.bmc.2014.07.017]

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

CARROZZO, Marina Maria;BATTISTI, UMBERTO MARIA;CANNAZZA, Giuseppe;PUJA, Giulia;RAVAZZINI, FEDERICA;BRAGHIROLI, Daniela;PARENTI, Carlo;
2014

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.
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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 / Carrozzo, Marina Maria; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Puja, Giulia; Ravazzini, Federica; Falchicchio, Aurelia; Perrone, Serena; Citti, Cinzia; Jozwiak, Krzysztof; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - STAMPA. - 22(2014), pp. 4667-4676. [10.1016/j.bmc.2014.07.017]
Carrozzo, Marina Maria; Battisti, UMBERTO MARIA; Cannazza, Giuseppe; Puja, Giulia; Ravazzini, Federica; Falchicchio, Aurelia; Perrone, Serena; Citti, Cinzia; Jozwiak, Krzysztof; Braghiroli, Daniela; Parenti, Carlo; Troisi, Luigino
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1060949
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