Clinically used proton pump inhibitors (PPIs) are not perfectly suitable for prolonged acid suppression because of the short plasma half-lives of 1–1.5 h. However, tenatoprazole, an imidazopyridine-type PPI, having a prolonged plasma half-life, is a promising replacement of the currently used PPIs. We have designed inhibitors that can possess imidazopyridine and imidazophosphorine units and can ease the formation of disulfide complex, which is one of the crucial steps toward the efficacy of PPIs. The M11L-SMD_Water/6-31++G(d,p)//M062X/6-31++G(d,p) level of theory-calculated results demonstrated that the acid activation of the imidazopyridine PPIs is complex than that of benzimidazole-type PPIs because of the presence of additional nitrogen, which could be protonated. However, the proton transfer from protonated pyridine nitrogen (PyNH⁺) to benzimidazole nitrogen(3) (BzN(3)) is more energetically favorable than that of protonated benzimidazole nitrogen(4) (BzN(4)H⁺) to BzN3 and the BzN(3)H⁺ further converts to the acid-activated sulfenic acid. It is to mention here that the PyNH⁺ PPIs are more stable compared to BzN(4)H⁺ PPIs. Subsequently, the acid-activated sulfenic acid forms the disulfide complex with the cysteine amino acid residue to inhibit the gastric proton pump H⁺,K⁺-ATPase. The disulfide complex formation (TS4) is the rate-determining step of the gastric proton pump inhibition process. The density functional theory (DFT) calculations also reveal that the acid activation and disulfide complex formation of all of the PPIs are very similar to those of potent PPI omeprazole. The free-energy activation barrier for tenatoprazole is 47.0 kcal/mol with respect to the preceding intermediate sulfenic acid, and the disulfide complex is stable by 28.0 kcal/mol. The M11L-SMD_Water/6-31++G(d,p) level of theory results reveal that the disulfide complex formation of the imidazophosphorine type of PPIs is marginally more favorable than that of the analogous imidazopyridine type of PPIs. The newly designed inhibitor-3 and inhibitor-5 possess the lowest activation free-energy barriers, i.e., 35.8 and 35.9 kcal/mol, respectively, in the rate-determining steps (TS4) and also achieve significant thermodynamic stability of the disulfide complex. Steered molecular dynamics simulations performed with representative tenatoprazole and inhibitor-5 corroborated the DFT results.