Hydrogen sulfide reduces omeprazole and is oxidized to polysulfides and elemental sulfur

Omeprazole is a medically used proton pump inhibitor. It covalently modifies the H⁺,K⁺-ATPase responsible for acid production in the stomach. Omeprazole itself is an inactive sulfoxide. At acidic pH, it produces a sulfenic acid derivative in equilibrium with a sulfenamide, able to inhibit the pump. These activated derivatives can react with a thiol (RSH) to form a mixed disulfide, which gives a thioether in the presence of reductants. Hydrogen sulfide (H₂S), while toxic at high concentrations, exerts signaling and cytoprotective roles. We hypothesized that omeprazole could react with H₂S to form the corresponding persulfide (RSSH), which could decay to a disulfide and the corresponding thiols; alternatively, the persulfide could react with another H₂S to give the thioether derivative. We confirmed the reaction of omeprazole with H₂S at pH 4.5 by UV-Vis spectrophotometry. The reaction occurred in a timescale of minutes and required acid. Turbidity appeared and reverted with the reductant tris(2-carboxyethyl)phosphine, suggesting the formation of polysulfides and elemental sulfur. These products were confirmed by cyanolysis, reaction with a sulfane sulfur probe (SSP4), Raman spectroscopy and UV-Vis detection of solubilized elemental sulfur. HPLC-UV-Vis and mass spectrometry demonstrated the formation of the thioether derivative of omeprazole. No evidence was obtained for the formation of the disulfide of omeprazole or its thiol reduction products. Computational modeling revealed that the formation of the thioether is kinetically preferred over the formation of the disulfide. Overall, our results show that acid-activated omeprazole reacts with H₂S forming the thioether derivative of omeprazole, polysulfides and elemental sulfur.