Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: Stereochemistry and tautomerism

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-S ¹⁰-O¹¹), D₂ (C²-S ¹⁰-C¹²-C¹³), and D₃ (S ¹⁰-C¹²-C¹³-N¹⁴) and two methoxy rotations defined by D₄ (C⁶-C⁵-O ⁸-C⁹) and D₅ (C¹⁶-C ¹⁷-0¹⁹-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.