Chemistry, pharmacology, and chiral separation of proton pump inhibitor drugs

Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 204 REVIEW article Chemistry, pharmacology, and chiral separation of proton pump inhibitor drugs Khadidja Addadi * , Nasser Belboukhari , and Khaled Sekkoum Bioactive Molecules and Chiral Separation Laboratory, Faculty of Exact Sciences, Tahri Mohammed’s University, Istiklal street, PO 417, Bechar 08000, Algeria * Author to whom correspondence should be addressed Received: February 01, 2025, Accepted: October 27, 2025, Published online: November 03, 2025 HOW TO CITE THIS Addadi K, et al. Chemistry, pharmacology and chiral separation of proton pump inhibitor drugs. Mediterr J Med Res. 2025; 2(4): 204-216. [Article number: 26]. https://doi.org/10.5281/zenodo.17525979 Keywords: Absolute configuration, chiral drug, enantioseparation, sulfoxide drug, omeprazole Abstract: A chiral sulfoxide is an important group in many bioactive molecules, and its absolute configuration often has substantial effects on its biological activity. Compounds that contain tri-coordinated sulfur atoms in a pyramidal structure can exist in different optically active forms. Omeprazole is a highly successful sulfoxide drug and the first registered substance in the proton pump inhibitor class, whose chirality may significantly impact its interaction with biological targets. The R-enantiomer of omeprazole is rapidly metabolized. In contrast, the clearance of the S-enantiomer occurs at a much slower rate. Viewing this, further attention should be paid to the pharmacological and toxicological studies of individual enantiomers of chiral drugs, and thus led to an exigent demand for enantioseparation. Introduction Chiral sulfoxides are in extremely high demand in nearly every sector of the chemical industry concerned with the design and development of new synthetic reagents, drugs, and functional materials [1]. The sulfoxide functional group is found in a large number of molecules of biological interest, many of which have application as pharmaceuticals for the treatment of a wide range of conditions [2]. Their chirality may play an important role in the interaction with biological targets and should be taken into consideration in drug design [3], Drug enantiomers often have different physiological actions. While much of this work centers on carbon chirality, sulfur has also been of concern. Many drugs and drug candidates containing sulfur have been synthesized or obtained as natural products [4]. This chapter centers around chiral sulfoxide drugs, covering their pharmacology, synthesis, and chiral separation. Sulfoxides: Chiral sulfoxides are used as a precursor of new chiral compounds, with interesting therapeutic properties. Sulfoxides constitute an important class of organosulfur compounds [3]. Such compounds feature a sulfinyl (S=O) functional group attached to two carbon atoms [5]. Though this structural motif is typically represented in Lewis structures as analogous to a carbonyl moiety, the sulfur atom of the sulfoxide is in fact a stereogenic centre when R1≠R2 (Figure 1). Figure 1: Lewis structures of sulfoxide group Copyright© 2025. This open-access article is distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 205 The oxygen and sulfur do not share a typical p-orbital pi bond which would enforce a planar conformation, but rather the oxygen donates electron density from a lone pair into a d-orbital of sulphur [6]. Chirality at pyramidal centers can be specified as (R) or (S) by the usual Cahn-Ingold-Prelog (CIP) system. To do so, valence bond structures are defined. If these structures are not self-evident, four conventions are used to define an appropriate valence-bond approximation for unsaturated compounds. Convention (b) states that contributions by d orbitals to bonds of quadriligant atoms are neglected. The absent ligand, normally alone electron pair, is assigned an atomic number of zero and in determining the sequence order of precedence, has the lowest priority. Thus, for methyl propyl sulfoxide, the priority sequence is O > C3H7>CH3. lone electron pair; the (2) enantiomer has the (R) configuration 1a-1c, Figure 2, [4]. Figure 2: Configurational assignments for sulfoxides and sulfonium salts In this and subsequent figures, 𝒆 indicates a lone electron pair In 1b and 2b, the group of lowest priority, 𝒆, is positioned away from the observer, 𝑶 Natural sulfoxide: Methionine S-oxide and biotin S-oxide: Sulfoxides contribute to unique bioactive (e.g., antioxidative, antimicrobial) properties of species from the Allium genus, particularly garlic and onion, which are long known and used in traditional medicine. Isolation, identification of these compounds, and revealing the mechanism of their action is of importance for the future design of pharmaceuticals Figure 3, [3]. Figure 3: Structure of A: Methionine S-oxide and B: biotin S-oxide Sulforaphane: Sulforaphane, a compound within the isothiocyanate group of organosulfur compounds, is a phytochemical commonly found in cruciferous vegetables such as broccoli, brussels sprouts and cabbage [7, 9]. Sulforaphane (1-isothiocyanate-4-methyl-sulfinylbutane), Figure 4 is a redox-active natural molecule isolated for the first time in 1958 from the leaves of hoary cress (Lepidium draba). Afterwards, in 1992, it was found in plants from the Brassicaceae family [8]. Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 206 Figure 4: Structure of sulforaphane Sulforaphane, which possesses antiproliferative, anti-inflammatory, anti-oxidant, and anti-cancer activities [9]. This compound has regulatory effects on the tumor cell cycle, apoptosis, and angiogenesis by modulation of the related signaling pathways and genes [3]. α-amanitin: Amanitins are members of the amatoxin family, toxic bicyclic octapeptides with molecular weights of about 900 g/mol, contained in certain fungi. Currently, three major families of fungi are known to contain these toxins: the amanita (Amanita sp.), the galerina (Galerina sp.), and the lepiota (Lepiotasp) [10]. α-amanitin (Figure 5) is a representative toxin found in the Amanita genus of mushrooms [11], and the consumption of mushrooms containing 𝛼-amanitincan lead to severe liver damage [12]. Due to its high selective inhibition of RNA polymerase II which is directly linked to its high toxicity, particularly to hepatocytes, α-amanitin received increased attention as a toxin-component of antibody drug conjugates in cancer research [13, 14]. Figure 5: Structure of 𝜶-amanitin Synthetised sulfoxide: Dimethylsulfoxide (DMSO) was first discovered in the 19th century as a byproduct at a chemical factory in Germany that was producing paper from wood pulp. In 1867, Russian chemist Alexander Saytzeff described the solvent characteristics of DMSO. Although it remained inconspicuous from the 1940s to 1950s, industrial researchers later uncovered that DMSO, when used as a solvent, could reinforce the permeability of herbicides, bactericides, antibiotics, and phytohormones, thereby boosting the growth of plants by 15.0%-20.0%. These findings demonstrated the efficacy of DMSO for food production and plant growth [15]. DMSO is an aprotic, amphiphilic solvent commonly used in biological studies to dissolve compounds with low solubility in water for in vitro and in vivo studies; it also serves as a cryopreservation agent [3]. DMSO has been used in several human therapeutic situations. In 1978, it received approval by the United States Food and Drug Administration (FDA) for use in the treatment of interstitial cystitis, by intravesical Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 207 instillation. Its effects do not seem to be related to a detectable histamine release from mast cells. It has been used successfully in the treatment of dermatological, urinary, pulmonary, rheumatic, and renal manifestations of amyloidosis. Basically, through its anti-inflammatory and reactive oxygen species scavenger actions, its use has been proposed in several gastrointestinal diseases [16, 17]. An improvement in the diffusion of a metal complex by coordination of a DMSO ligand was noted (Figure 6). In a search for a more selective alternative to cisplatin and its analogs, high hopes were put on NAMI-A, a ruthenium (III) complex [ImH] [transRuCl4(DMSO) (Im)] (Im=imidazole) bearing S-coordinated dimethylsulfoxide [3]. Figure 6: Complexes containing dimethylsulfoxide ligand(s) NAMI-A Modafinil: Figure 7, Modafinil (d, l-2- [(diphenyl methyl) sulfinyl] acetamide; is a novel wake promoting agent is for oral administration [18], first marketed in France in the early 1990s, as a treatment for the excessive somnolence as a feature of narcolepsy. In 2008 approved by the United States FDA as a schedule IV agent to treat excessive daytime sleepiness in narcolepsy, shift work sleep disorder, and obstructive sleep apnea/hypopnea syndrome [19]. Figure 7: Structure of modafinil It is a white to off-white crystalline solid that is practically insoluble in water and cyclohexane and slightly soluble in methanol and acetone. The molecular formula is C15H15NO2S and the molecular weight is 273.4 [18]. Although typically prescribed in racemic form, both enantiomers are biologically active. However, the isomers exhibit different pharmacokinetic profiles. The S-isomer has a relatively short terminal elimination half-life of 4-5 hrs, compared with that of the R-isomer, which is approximately 3-4 times longer (~15 hours). The (S)-isomer is eliminated from the body at a rate three times faster than that of the R-isomer [20, 21]. Sulindac: Figure 8, Sulindac{(Z)-5-fluoro-2-methyl-I-[4-(methylsulphinyl) phenyl] methylene]-1H-indene3-acetic acid; is a nonsteroidal anti-inflammatory drug (NSAID) structurally similar to indomethacin [22]. The anti-inflammatory drug sulindac is employed in the treatment of arthritic conditions and has, over the past ten years, gained interest as an anti-cancer treatment. Four neurokinin antagonists have been investigated for their potential for use in treatments against depression, urinary incontinence and asthma [2]. Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 208 Figure 8: Structure of sulindac Cenicriviroc: (S)-8-[4-[2-(butoxy) ethoxy] phenyl]-1-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl) methyl] sulfinyl] phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide methane sulfonate (Figure 9) [23]. Figure 9: Structure of cenicriviroc Cenicriviroc is a drug candidate developed by Takeda Pharmaceutical Company as an orally bioavailable inhibitor of two chemokine receptors CCR2 and CCR5 with potent anti-HIV-1 activity with a favorable pharmacokinetic profile in humans. The ability to inhibit macrophages in the peripheral fat tissue led to its evaluation for the treatment of nonalcoholic steatohepatitis (ASH), a progressive form of non-alcoholic fatty liver disease (NAFLD) [3]. Adezmapimod: It is a tri-substituted imidazole based p38 MAP kinase inhibitor in the pyridinyl imidazoleclass that is widely used in the literature as an ATP-competitive ref [24], and it is an anti-inflammatory drug [25]. In the 1990s, a series of pyridylimidazoles were developed at SmithKline Beecham as kinase inhibitors, and a sulfoxide derivative (Figure 10) was identified as a potent inhibitor of stress-activated p38 mitogenactivated protein kinase (MAPK) [3]. Figure 10: Structure of Adezmapimod Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 209 Sulfoxides as proton pump inhibitors: Sulfoxides bearing bezimidazole and pyridine moieties have evolved as first-line treatment of peptic ulcers and gastroesophageal reflux disease. We will thoroughly explore this specific category of medications in the next section. Proton pump inhibitor drugs; Synthesis and pharmacology, a very successful sulfoxide drug is the proton pump inhibitor, omeprazole. Investigated in the late 1970s, it was marketed as Losec1 (Europe, 1988) and as prilosec1 (USA, 1990). Sales quickly approached US $6 billion per annum, and Prilosec1 is now available over the counter in the USA. Omeprazole, marketed as a racemate, is a prodrug, the active agent being an achiral sulfenamide formed by biotransformation [4]. The first representatives of this group, timoprazole, picoprazole, and omeprazole were developed in the late 1970s, and the latter was finally selected, followed by lansoprazole, pantoprazole, and rabeprazole, Figure 11, [3]. Compounds which contain tricoordinated sulfur atoms in a pyramidal structure can exist in different optically active form, omeprazole, 5-methoxy-2-(((4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl) sulfinyl)- 1Hbenzimidazole [26], is a well-known gastric proton pump inhibitor (PPI) used in the treatment of gastricacid related diseases [27]. Omeprazole was first approved as a racemic mixture, but the (S)-enantiomer was later introduced to the market. The major difference is that (S)-omeprazole is metabolized more slowly and reproducibly than the (R)-omeprazole and racemic omeprazole. Ilaprazole is a new PPI, designed for the treatment of gastric ulcers developed by Il-Yang Pharmaceutical [28]. Pantoprazole, (5‐(difluoromethoxy) ‐ 2‐[(3,4‐dimethoxy‐2‐pyridyl) methylsulfinyl]‐1H‐benzimidazole) (Scheme 1) [29], and Lansoprazole (2- [[3 methyl-4-(2,2,2-trifluoroethoxy) pyridin2-yl] methylsulfinyl]-1H benzimidazole) [30]. Figure 11: Chemical structures of drugs IPP (A) omeprazole (B)esomeprazole (C) pantoprazole and (D) lansoprazole Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 210 Synthesis: In 1986, Branstrom et al., who developed omeprazole at Astra Pharmaceuticals, published a process for the preparation of omeprazole and its intermediates in the United States (Scheme 1) [2]. Scheme 1: Synthesis of omeprazole through Branstrom et al 2,3, Trimethyl pyridine 1 was oxidized by hydrogen peroxide in acetic acid to give the N-oxide 2, and the latter was nitrated using a mixture of sulfuric acid and nitric acid to give the 4-nitro derivative 3 [2, 31]. The nitro group in 3 was displaced by hydroxymethylation to yield 4. Treatment of compound 4 with acetic acid anhydride reduces the ring and forms an ester derivative 5. The corresponding alcohol 6 was formed by the treatment with base, followed by displacement of the hydroxyl group with a chloride using thionyl chloride to give 2-chloromethyl-4-methoxy-2,3,5-trimethyl pyridine 7. Omeprazole 10 was obtained through the reaction of thiol 8 with pyridine 7 in the presence of NaOH; oxidation of pyrmetazole sulfide with mCPBA gave 10 as a racemic mixture [2, 31]. Bhalero and coworkers reported a novel synthetic route to omeprazole 5, via the formation of the benzimidazole ester 2 and subsequent in situ reaction with the pyridyl Grignard intermediate 4 (Scheme 2) [2]. Cotton et al. described an innovative method for the asymmetric synthesis of esomeprazole. The (S)-enantiomer of omeprazole was synthesized through the asymmetric oxidation of prochiral sulfide 5methoxy-2-[[(4-methoxy-3,5-dimethyl pyridin-2-yl) methyl] thio]-1H-benzimidazole 1 (Scheme 3) [2, 31]. Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 211 The key step involved titanium-mediated oxidation using cumene hydroperoxide in the presence of (S, S)- diethyl tartarate (DET). Enantioselectivity was achieved by carefully preparing the titanium complex in the presence of sulfide 1 at an elevated temperature and/or during an extended preparation time. Additionally, performing the oxidation of sulfide 1 in the presence of an amine further contributed to the impressive enantioselectivity, resulting in a remarkable 94.0% enantiomeric excess (ee) [2, 31]. Scheme 2: Synthesis of omeprazole via the formation of the benzimidazole ester Scheme 3: Asymmetric synthesis of S-omeprazole Large-scale oxidations from the pharmaceutical industry, giving omeprazole4 from pyrmetazole1 have been reported which use inorganic oxidants such as sodium perborate, sodium hydrochloride, or sodium percarbonate in the presence of Mo catalysts (Scheme 4) [2]. Pharmacology and mechanism of action: Proton-pump inhibitors (PPIs) have emerged as the drug class of choice for treating patients with acid-related diseases, including gastroesophageal reflux disease (GERD), duodenal ulcer, and gastric ulcer. PPIs are also effective in treating patients with Barrett’s esophagus and Zollinger-Ellison syndrome [32]. The stimulation of proton pump (H+, K+-ATPase) in the parietal cell represents the final step of acid secretion and this knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at blocking this enzyme [28, 33-38], Figure 12. Chemically, all the available PPIs consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors of gastric acid secretion available [37]. Mediterranean Journal of ISSN: 2789-1895 https://mrj.org.ly Medical Research Mediterr J Med Res Nwaneri MGU, et al. Mediterr J Med Res. 2025; 2(4): 204-216. Page 212 Figure 12: Control of gastric acid secretion from the parietal cell Acid secretion from the parietal cell is stimulated by acetylcholine (ACh), histamine and gastrin. Gastrin and ACh also reinforce acid secretion by causing the release of histamine from the enterochromaffin-like (ECL) cells, which lie close to the parietal cells in the gastric pits. Prostaglandin E2 (PGE2) reduces acid secretion. The sites of action of the main drugs used to inhibit acid secretion from the parietal cell are shown. There are no useful inhibitors of gastrin action, and the gastric-selective muscarinic receptor (M-1) antagonist pirenzepine is no longer available in the United Kingdom. H2, Histamine type 2 receptor [38]. Under acid conditions omeprazole 1 is transformed to the spiro intermediate 2 which arises as a result nucleophilic attack of the pyridine nitrogen on the C2-position of the protonated benzimidazole 3. Aromatization to the sulfenic acid4is followed by dehydration to the tetracyclic sulfenamide5which reacts with the target enzyme and deactivates it via formation of the disulfide complex 6 (Scheme 5) [2]. Pharmacodynamics and pharmacokinetics of IPPS drugs: All PPIs suppress gastric acid secretion by blocking the gastric acid pump, H+/K+-ATPase [39]. Figure 13, which was analyzed by Besancon, illustrates the variations in the rate of inhibition of H+/K+-ATPase activity with four PPIs [39, 40]. Figure 13: The rate of inhibition of the gastric H+, K+-ATPase under acid-transporting conditions by rabeprazole, omeprazole, lansoprazole, and pantoprazole. The vesicles were incubated in 150 mM KCl, with 1 mg/ml valinomycin in buffer at pH 6.8 in the presence of 10 mM compound and the reaction started by the addition of MgATP [40].