Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.

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A systematic and comprehensive study of the conformational spaces of the Cinchona alkaloids quinine, quinidine, cinchonine, cinchonidine, epiquinine, epiquinidine, epicinchonine, and epicinchonidine using the semiempirical PM3 method is described. The results were analyzed in terms of syn/anti and open/closed/hindered and alpha/beta/gamma conformations. Special emphasis was given to the torsion angles T(1) (C(4a')-C(4')-C(9)-C(8)), T(2) (C(4')-C(9)-C(8)-N(1)) and T(3) (H-O(9)-C(9)-C(8)) that define the backbone and the hydroxy conformation, respectively. The results reveal the quasi-enantiomeric relationships between quinine and quinidine and between epiquinine and epiquinidine, and the main structural differences that exist between the therapeutically active Cinchona alkaloids, quinine and quinidine, and their inactive epimers, epiquinine and epiquinidine. The lowest energy conformation of quinine and quinidine is anti-closed-alpha. The lowest energy conformations of epiquinine and epiquinidine are anti-open-beta and anti-open-alpha, respectively. Low energy conformations with an intramolecular hydrogen bond (N(1.)H(.)O(9)) were found in epiquinine (the global minimum) and epiquinidine, but not in quinine and quinidine.

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A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3-C2-S10-O11), D2 (C2-S10-C12-C13), and D3 (S10-C12-C13-N14) and two methoxy rotations defined by D4 (C6-C5-O8-C9) and D5 (C16-C17-O19-C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer.

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