Fig. 4. The mechanism of activation of the proton pump inhibitors shown in general structural form. The substituent R
1, R
2, R
3 and R
4 of the general structure (Bz-Py) represent a substituent chosen from hydrogen, methoxy, methyl and substituted alkoxy group. Top part shows the protonation of the pyridine ring and the second row of structures shows protonation also of the benzimidazole ring. The bis-protonated forms are in equilibrium with the protonated benzimidazole and unprotonated pyridine. In brackets is shown the mechanism of activation whereby the 2C of the protonated benzimidazole reacts with the unprotonated fraction of the pyridine moiety that results in rearrangement to a permanent cationic tetracyclic sulfenic acid which in aqueous solute dehydrates to form a cationic sulfenamide. Either of these thiophilic species can react with the enzyme to form disulfides with one or more enzyme cysteines accessible from the luminal surface of the enzyme. Adapted from Shin et al.
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