Abstract
1,4-Dihydropyridine (DHP) scaffold holds an outstanding position with its versatile pharmacological properties among all heterocyclic compounds. Although most of the commercially available DHPs are marketed as a racemic mixture, the chiral center at C-4 can lead to even opposite pharmacological activities between the enantiomers. In the present study, enantioseparation of seventeen DHP structural analogues, consisting of either pharmacologically active or newly synthesized derivatives, (M2-4, MD5, HM2, HM10, CE5, N11, N10, N7, M11, MC6-8, MC13, MD23, and 42IIP) by high-performance liquid chromatography was investigated using immobilized polysaccharide-based chiral stationary phase, Chiralpak IC column. Due to the solvent versatility of the covalently immobilized chiral stationary phase in enantiomer separation, multiple elution modes including standard normal phase, nonstandard mobile phase, and reversed phase were used to expand the possibility to find the optimum enantioselective conditions for the tested analytes. Under appropriate separation conditions, complete enantiomeric separation was obtained for nearly all compounds except MC6-8 and MC13 which contained two chiral centers. Additionally, the effects of the polar modifier, the additive, and column temperature on the chiral recognition were evaluated. The thermodynamic parameters calculated according to the linear van’t Hoff equation indicated that the chiral separations in this study were enthalpy-driven or entropy-driven. Some parameters of method validation such as linearity, limit of quantitation, and repeatability were also measured for all studied compounds to prove the reliability of the method.
Highlights
1,4-Dihydropyridine (DHP) nucleus is one of the most important heterocycles due to its wide variety of biological activities
N10 was a selective T-type Cav3.2 blocker with significant analgesic effects [5]. These compounds were tested as racemates in their original cited works, the enantiomeric resolution is of utmost importance for DHPs because the chiral center at C-4 can lead to even opposite pharmacological activities between the enantiomers [6]
Injection repeatability of six consecutive runs gave relative standard deviations (RSDs) of less than 3%. These results suggest that the present method is effective for the separation and quality control for the newly synthesized structural analogues during their every process
Summary
1,4-Dihydropyridine (DHP) nucleus is one of the most important heterocycles due to its wide variety of biological activities. N10 was a selective T-type Cav3.2 blocker with significant analgesic effects [5] These compounds were tested as racemates in their original cited works, the enantiomeric resolution is of utmost importance for DHPs because the chiral center at C-4 can lead to even opposite pharmacological activities between the enantiomers [6]. Some studies on applications of the immobilized CSPs for chiral separation of DHPs have been reported [12,13,14,15], the enantiomeric resolution of DHP based hexahydroquinolines, which provide promising scaffolds for the development of novel calcium channel blockers, has not been investigated yet. The Chiralpak IC column was selected for further investigation
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