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. - 22:17(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.
2014
22
17
4667
4676
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. - 22:17(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, ...espandi
File in questo prodotto:
File Dimensione Formato  
Carozzo2014.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 1.69 MB
Formato Adobe PDF
1.69 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1060949
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 11
social impact