(H+-K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 3. Evidence for the involvement of a sulfenic acid in their reactions

Abstract

The (H+-K+)-ATPase inhibiting sulfoxides la,b undergo acid-induced transformations into the cyclic sulfenamides 2a,b via the putative sulfenic acids 4a,b. At high concentrations mixtures of 2a,b and thiosulfinates 5a,b were obtained. In contrast, IC, which cannot form 2, is completely transformed under similar conditions into 5c, the anhydride of 4c. The temperature-dependent equilibrium between 2a and 5a and the kinetics of the ring opening of 2a by water provide evidence for the sulfenic acid 4 as an intermediate involved in the pH-dependent transformations of 1. The thiossulfnates 5 decompose mainly to the disulfides 6 at a rate depending on the solvent and conditions and are also reduced to 6 by thiols. The dimeric ylide 7a could be isolated from 6a (prepared in situ from la as well as from 2a). The symmetrical disulfides 6 and 7 are cleaved by thiols to yield the mixed disulfides 3 and the thiols 8. Similarly, cleavage of 3 liberates an additional equivalent of 8. Finally, the unstable thiols 8 are removed from the thiol-disulfide interchange equilibrium by irreversible rearrangement to the sulfides 9.

Intramolecular Nonbonded S...N Interaction in Rabeprazole

“…4. The generation of 8e, 8f, 9, and cystine definitely suggest that sodium rabeprazole (1) also inhibits the gastric (H ϩ -K ϩ )-ATPase in the action mechanism reported previously, [18][19][20] and the same intramoleculer nonbonded S · · · N interactions will also exist in the other inhibitors of the gastric (H ϩ -K ϩ )-ATPase such as lansoprazole 24) and omeprazole. 25) In conclusion, the intramoleculer nonbonded S · · · N interactions in the crystal structures of rabeplazole derivatives 7a-d and the intermolecular nonbonded S · · · N interaction between ethylmethylsulfoxide S and N of the pyridine moiety in a solution were recognized.…”

“…Subsequently, the intermediates, which were formed in the reaction cascade [17][18][19][20] 18) Using 60% HClO 4 , the perchlorate salt 8f was obtained in a quantitative yield, as shown in Chart 3. The reaction of 8e with ethanethiol gave the desired disulfide 9 in 99% yield, as shown in Chart 4.…”

“…14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety.…”

“…13,14) As a result of the investigations on the mechanism of action of these inhibitors, it has been expected that 1 will be activated by protonation in the parietal cell (intermediate 2), converted into the sulfenamide 5 via the spiro sulfoxide 3 and sulfenic acid 4, and the active principle 5 can react with the accessible cysteines of the gastric (H ϩ -K ϩ )-ATPase followed by the inhibition of the enzyme (compound 6), as shown in Chart 1. 14,[17][18][19][20] In this reaction cascade, the key step is the formation of the putative spiro sulfoxide 3 arising from nucleophilic attack of the pyridine nitrogen on the activated 2-position of the benzimidazole moiety. 18) The fact that the nucleophilic attack of the pyridine nitrogen smoothly proceeds despite the week nucleophilicity is very interest, and made us guess that the intramoleculer nonbonded S · · · N interaction influenced this step.…”

Activation and Stabilization of Drugs by Supramolecular pKa Shifts: Drug‐Delivery Applications Tailored for Cucurbiturils

“…The proton-pump inhibitors 1 were subsequently selected as medicinally relevant benzimidalzoles [14][15][16] with the idea of utilizing supramolecular pK a shifts for the activation and stabilization of these drugs. The reaction pathways of 1 have been the subject of intensive mechanistic investigations (Scheme 1).…”