Chirality of β2-agonists. An overview of pharmacological activity, stereoselective analysis, and synthesis

Abstractβ2-Agonists (β2-adrenergic agonists, bronchodilatants, and sympathomimetic drugs) are a group of drugs that are mainly used in asthma and obstructive pulmonary diseases. In practice, the substances used to contain one or more stereogenic centers in their structure and their enantiomers exhibit different pharmacological properties. In terms of bronchodilatory activity, (R)-enantiomers showed higher activity. The investigation of stereoselectivity in action and disposition of chiral drugs together with the preparation of pure enantiomer drugs calls for efficient stereoselective analytical methods. The overview focuses on the stereoselectivity in pharmacodynamics and pharmacokinetics of β2-agonists and summarizes the stereoselective analytical methods for the enantioseparation of racemic beta-agonists (HPLC, LC-MS, GC, TLC, CE). Some methods of the stereoselective synthesis for β2-agonists preparation are also presented.

Chiral Aspects of Local Anesthetics

Thanks to the progress made in chemical technology (particularly in the methodologies of stereoselective syntheses and analyses) along with regulatory measures, the number of new chiral drugs registered in the form of pure enantiomers has increased over the past decade. In addition, the pharmacological and pharmacokinetic properties of the individual enantiomers of already-introduced racemic drugs are being re-examined. The use of the pure enantiomer of a drug that has been used to date in the form of a racemate is called a “chiral switch”. A re-examination of the properties of the pure enantiomers of racemates has taken place for local anesthetics, which represent a group of drugs which have long been used. Differences in (R) and (S)-enantiomers were found in terms of pharmacodynamic and pharmacokinetic activity as well as in toxicity. Levobupivacaine and robivacaine were introduced into practice as pure (S)-(−)-enantiomers, exhibiting more favorable properties than their (R)-(+)-stereoisomers or racemates. This overview focuses on the influence of chirality on the pharmacological and toxicological activity of local anesthetics as well as on individual HPLC and capillary electrophoresis (CE) methods used for enantioseparation and the pharmacokinetic study of individual local anesthetics with a chiral center.

Crystal structures of racemic and enantiopure synephrine correlated with physicochemical properties from IR spectroscopy and thermal analysis

The proto-alkaloid synephrine {SYN; systematic name: 4-[1-hydroxy-2-(methylamino)ethyl]phenol}, C9H13NO2, is found to crystallize as a neutral molecule in the racemate and as a zwitterion in the pure enantiomer, in which the phenolic H atom has been transferred to the amino group. In the racemate crystal, an enantiomeric pair on an inversion centre is weakly linked by alcoholic O—H and N—H groups into an R 2 2(10) ring. The trigonal pyramidal amino group is also linked to the phenolic and alcoholic groups to form a C(6) chain. In the enantiopure crystal, the deprotonated phenolic O atom is involved in trifurcated hydrogen bonding to two quaternary ammonium groups and an alcoholic O—H group to form a fused R 2 4(11) ring and a C(7) chain. From the results of the crystal structure analysis, thermal analyses and DFT calculations validated from FT–IR spectra, a different tautomer was found in the racemic molecule (RS-SYN) versus the enantiopure molecule (R-SYN).

Enantiomerically pure and racemic dimethyl{N-[(2-oxidonaphthalen-1-yl-κO)methylidene]valinato-κ2N,O}tin(IV)

The title compound, [Sn(CH3)2(C16H15NO3)], crystallized from one reaction batch with high enantiomeric excess as both a pure enantiomer and a racemate. TheSenantiomer crystallizes in the chiral space groupP32. The racemate crystallizes in the space groupP\overline{1} withRandSenantiomers in the crystal lattice; these form dimers about a crystallographic inversion centre.

Enantiomerically pure (1S,5R) and racemic 3-(1-benzothiophen-2-yl)-8-azoniabicyclo[3.2.1]oct-2-ene acetate

The title compound, C15H16NS+·C2H3O2−, has been crystallized as both a pure enantiomer (1S,5R) and a racemate. The racemate crystallizes in the space groupCc, with molecules of opposite handedness related to each other by the action of thec-glide. The enantiomer is essentially isostructural with the racemate, except that the glide symmetry is violated by interchange of CH and CH2groups within the seven-membered ring. The space-group symmetry is reduced toP1 with two molecules in the asymmetric unit. The enantiomer structure shows disorder of the thiophene ring for one of the molecules in the asymmetric unit. The major component of the disorder has the thiophene ring in the same position as in the racemate, but generates a higher-energy molecular conformation. The minor disorder component has different intermolecular interactions but retains a more stable molecular conformation.