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.

7-Chloro-5-(furan-3-yl)-3-methyl-4H-benzo[e][1,2,4]thiadiazine 1,1-Dioxide as Positive Allosteric Modulator of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor. The End of the Unsaturated-Inactive Paradigm?

“…Focusing our interest on these metabolites, we evaluated the activity of compounds 2 and 3 as AMPA-PAMs by patch-clamp technique using the parent compound 1 as reference. In order to compare the current activity data to compounds previously published by our group, the same methodology was selected. ,, Compounds 1 , 2 , and 3 were tested at the concentration of 10 μM in primary cultures of cerebellar granule neurons. Figure shows the potentiation of the kainate (KA)-evoked currents by the three tested compounds.…”

“…In fact, chemical degradation of a pharmacologically active compound can lower the intended concentration below the therapeutic dose. Additionally, it has been shown that the AMPA-PAM activity resides in mainly one enantiomer . Thus, it is necessary to obtain the single enantiomers to perform single pharmacological tests.…”

A Metabolomic Approach Applied to a Liquid Chromatography Coupled to High‐Resolution Tandem Mass Spectrometry Method (HPLC‐ESI‐HRMS/MS): Towards the Comprehensive Evaluation of the Chemical Composition of Cannabis Medicinal Extracts

“…On the basis of our research group's considerable experience in LC–MS and LC–MS/MS analysis (Carrozzo et al, , , ; Cannazza et al, , ; Battisti et al, ), we developed a chromatographic method exploiting the metabolomic approach. The mobile phase employed was water/acetonitrile with 0.1% formic acid ( v / v ) with a linear gradient from 5% to 95% acetonitrile in 45 min and a total run time of 65 min.…”

Recent Functionalizations of Primary Sulfonamides

“…Cannazza and co-workers prepared biologically active sultam derivatives through an intramolecular ring closure between a sulfonamide amine moiety and an amide functional group, followed by a second intramolecular ring closure and imine reduction to give tricyclic products (Scheme 94). 235 ortho-Aminobenzenesulfonamide was used as a diamine starting material by Ruijter and co-workers to form the relevant heterocycle by palladium-catalyzed aerobic oxidative isocyanide insertion (Scheme 95). 236 Lv and co-workers explored the copper(I) iodide catalyzed domino S N 2′/coupling reaction of Baylis-Hillman acetates and nucleophiles such as sulfonamides.…”