Determination of the absolute configuration and solution conformation of the antifungal agents ketoconazole, itraconazole, and miconazole with vibrational circular dichroism

Abstract

The absolute configuration assignments of three antifungal agents, (+)-(2R,4S)-ketoconazole, (+)-(2R,4S)-itraconazole (with (S)-configuration at the sec-butyl group) and (+)-(S)-miconazole nitrate have been confirmed by using vibrational circular dichroism (VCD). For these three antifungal drugs, this study also provides evidence for the most abundant conformations of miconazole and for the relative conformations of the azole, dichlorophenyl, and methoxyphenyl groups in ketoconazole and itraconazole, in chloroform solution.

Application of chiral technology in a pharmaceutical company. Enantiomeric separation and spectroscopic studies of key asymmetric intermediates using a combination of techniques. Phenylglycidols

“…[37][38][39] More recently, the spectroscopic approach of comparing observed and calculated vibrational circular dichroism (VCD) spectra, electronic circular dichroism (ECD), or optical rotation (OR) values has gained popularity due to the ease of data acquisition and the ability to calculate spectra and values with commercially available software and supercomputers or modern, powerful PCs and Linux clusters. [40][41][42][43][44][45][46][47][48][49] In the case of VCD, besides absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [50][51][52][53] additional information can be obtained, including solution conformation 54,55 and real-time reaction monitoring. 56,57 VCD has been applied specifically to pharmaceuticallyrelevant molecules.…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…[328][329][330] VCD has been used to determine the absolute stereochemistry of natural products, 320,331 compounds derived via asymmetric enzymatic catalysis, 332 as well as carboxylic acids 333,334 and alcohols 204 in derivatized form in order to improve calculations by obviating the presence of dimers or rigidifying the molecule of interest, respectively. There are numerous published examples of VCD being applied specifically to pharmaceutically-relevant molecules, 325,335,336 as well as numerous reports where various permutations of calculated versus measured VCD, ECD and/or OR have been used to determine absolute configuration. [337][338][339][340] The combination of calculated versus measured VCD and NMR, 341 CD using porphyrin tweezers and NMR, 342 and calculated versus measured CD plus X-ray analysis have also been reported.…”

“…Besides determining absolute stereochemistry of molecules containing one or more asymmetric centers, or planes or axes of asymmetry, i.e., atropisomerism, [319][320][321][322][323][324] additional information about solution conformation can be obtained. 304,[325][326][327] Also, VCD can be used for real-time reaction monitoring. [328][329][330] VCD has been used to determine the absolute stereochemistry of natural products, 320,331 compounds derived via asymmetric enzymatic catalysis, 332 as well as carboxylic acids 333,334 and alcohols 204 in derivatized form in order to improve calculations by obviating the presence of dimers or rigidifying the molecule of interest, respectively.…”

HPLC separation and VCD spectroscopy of chiral pyrazoles derived from (5R)-dihydrocarvone

“…13 C NMR variable temperature in the liquid state and 13 C CPMAS NMR spectroscopy in the solid state were two successful methods used to determine the activation barriers, the tautomeric equilibrium and 13 C signal assignments. 11 For instance, in benzimidazoles, 12 used as pharmaceuticals such as esomeprazole (a chiral switch of omeprazole, an efficient anti-ulcer agent), the tautomeric equilibrium was only studied by NMR spectroscopy 13 and by X-ray crystallography. 14 Recently, an exhaustive conformational analysis has been conducted on this molecule by using DFT calculations.…”