Determination of kinetic parameters of enantiomerization of benzothiadiazines by DCXplorer

Abstract

Benzothiadiazines differently substituted at the sulfonamidic nitrogen atom, at the stereogenic carbon atom and at the anilinic nitrogen atom have been synthesized and fully characterized. Enantioseparation of these compounds has revealed rapid on-column enantiomerization. The recently developed software DCXplorer has been successfully applied to calculate enantiomerization kinetic parameters. Enantiomerization barriers of 3-phenyl substituted benzothiadiazines, calculated in this work, have indicated a higher enantiomerization rate suggesting that the aromatic substituent exerts a strong effect on the enantiomerization process. Methyl substitution on N(2) position led to higher free energy barriers of enantiomerization, suggesting negative influence of methyl in the N(2) position on enantiomerization kinetics. However, methylation on N(4) position increases the enantiomerization rates significantly. The results obtained have been employed to postulate an enantiomerization mechanism for chiral benzothiadiazine type compounds.

Molecular modeling studies, synthesis, configurational stability and biological activity of 8-chloro-2,3,5,6-tetrahydro-3,6-dimethyl-pyrrolo[1,2,3-de]-1,2,4-benzothiadiazine 1,1-dioxide

“…No epimerization occurred during separation on a Chiralcel OD column using non aqueous solvents as mobile phase (hexane/2-propanol). These data are in accordance with our previous studies that indicated a rapid enantiomerization in aqueous solvents at chiral carbon C3 of 2,3-dihydrobenzothiadiazine type compounds structurally related to 1 [22][23][24][25][26][27][28] . Docking of (3S,6R)-1 (a) and (3S,6S)-1 (b) at the GluA2 dimer interface (hydrophobic residues are in blue, hydrophilic residues are in red).…”

“…Previous studies on the chemical stability of benzothiadiazines structurally related to 1, like IDRA21, indicated their rapid hydrolysis in acidic solvents. [22][23][24][25][26][27][28] Further studies have suggested that IDRA21, when orally administered, hydrolyzes in 2-amino-5-chlorobenzensulfonamide, which was detected at high levels in rat brain together with single enantiomers of IDRA21 itself. 50 The data obtained with the sf-BD-rHPLC method indicate that 1 is more stable to hydrolysis than IDRA21 under acidic conditions.…”

“…Since it is known that chiral 2,3-dihydrobenzothiadiazines are configurationally labile, it became important to evaluate the stability of single stereoisomers of 1 in order to obtain reliable pharmacological results. [22][23][24][25][26][27][28] With this aim, the stopped-flow bidimensional recycling HPLC (sf-BD-rHPLC) method, recently developed by our research group, was employed to investigate stereo and chemical stability of 1 under conditions similar to those of pharmacological experiments. 26,27 2.…”

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

“…26 Since we have recently reported a rapid enantiomerization in aqueous solution and a rapid hydrolysis in acid medium of IDRA21 and related compounds, a primary goal of the present work is to develop a compound with high configurational and chemical stability under conditions similar to those that they will meet in vivo. [27][28][29][30][31][32][33][34][35] One of the most relevant IDRA21 derivatives, 2,3,3a,4-tetrahydro-1Hpyrrolo [2,1- Fig. 1) reached clinical trials due to its ability to act as cognitive enhancing agent in normal young and aged rodents.…”

Chiral 1,2‐Dialkenyl Diaziridines: Synthesis, Enantioselective Separation, and Nitrogen Inversion Barriers

“…Peak coalescence was observed for 1,2-diallyldiaziridine 1 at 170°C. The reaction rate constant of enantiomerization k 1 were determined by unified equation of chromatography, [36][37][38][39][40][41] which allows a direct, fast and precise evaluation of the experimental peak profiles. For the evaluation of the activation parameters of enantiomerization of 1,2-diallyldiaziridine 1 experiments between 105 and 145°C (5°C steps) were considered.…”