Conformational enantiomers of drugs and drug-like molecules: a combined investigation by chromatographic, spectroscopic and computational methods.
The enantiomers of chiral molecules differ in their biological activity, therefore there is a large interest in the production of pure enantiomers in the pharmaceutical, fine chemical, food and agrochemical industries. Molecular chirality includes a variety of closely interconnected static and dynamic stereochemical aspects that are all related to the three-dimensional structure of molecules. While static stereochemistry focuses on the spatial arrangement of atoms and groups in molecules and the corresponding chemical and physical properties, dynamic stereochemistry stresses structural changes as observed in asymmetric reactions as well as during interconversion of con¿gurational and conformational isomers. While static stereochemistry and its consequences on biological activity of drugs are well recognized and understood, the dynamic counterparts of stereochemistry and chirality are less studied and their impact on drug action are studied to a lesser extent. Diazepam (an anticonvulsant, skeletal muscle relaxant, anxiolytic drug) and other structurally related 1,4-benzodiazepin-2-ones (BDZ) lacking a chiral center exist in the form of conformational enantiomers. The two enantiomers interconvert quickly at room temperature by a ¿ring-flip¿ mechanism, and can be separated by chromatography (HPLC) on chiral stationary phases (CSPs) at low temperatures. Depending on the substitution pattern on the N1 of the azepine ring, enantiomerization rate can be slowed compared to diazepam and the half-life of the individual enantiomers raised up to the minute or hour time scales. Here we propose to investigate by chromatographic, spectroscopic, kinetic and computational methods the dynamic stereochemistry of chiral benzodiazepine-2-ones related to diazepam. The new data generated by the project can give useful insights for a better understanding of the dynamic aspects of drug-receptor interaction and guide the design of new drugs with improved properties.