Sulfoximine derivatives — their pharmacochemical properties, synthesis, and potential in drug discovery
DOI:
https://doi.org/10.56782/pps.626Keywords:
sulfoximine derivatives, new drug candidates, chemical space, drug discovery, organosulfur compoundsAbstract
Currently, pharmaceutical chemists are focusing on investigating an increasingly wide range of compounds as potential new drugs, including substances of natural origin and those obtained by chemical synthesis. Due to the advancements in experimental techniques, modern science possesses numerous tools for discovering new types of biologically active molecules. For example, the development of chemical synthesis methods has created the possibility to reach completely new arrays of compounds, as potential candidates for some new drugs. In this context, sulfoximines have quite recently emerged as a promising and versatile class of organosulfur compounds with interesting pharmacological properties. In this article, we present an overview of the key features of the sulfoximine functional group, including its unique pharmacochemical profile, that may elevate its potential in medicinal chemistry. We also briefly discuss examples of synthetic approaches to obtain new derivatives containing this functional group, with particular attention to both classical and modern synthetic protocols. Finally, selected examples of biologically active sulfoximines developed by various research groups are highlighted, demonstrating their potential applications in drug discovery.
Downloads
References
1. Borst, M.L.G.; Ouairy, C.M.J.; Fokkema, S.C.; Cecchi, A.; Kerckhoffs, J.M.C.A.; De Boer, V.L.; van den Boogaard, P.J.; Bus, R.F.; Ebens, R.; van der Hulst, R.; Knol, J.; Libbers, R.; Lion, Z.M.; Settels, B.W.; de Wever, E.; Attia, K.A.; Sinnema, P.-J.; de Gooijer, J.M.; Harkema, K.; Hazewinkel, M.; Snijder, S.; Pouwer, K. Polycyclic Sulfoximines as New Scaffolds for Drug Discovery. ACS Comb. Sci. 2018, 20(6), 335–343. DOI: 10.1021/acscombsci.7b00150
2. Manning, J.M.; Moore, S.; Rowe, W.B.; Meister, A. Identification of L-Methionine S-Sulfoximine as the Diastereoisomer of L-Methionine SR-Sulfoximine That Inhibits Glutamine Synthetase. Biochemistry 1969, 8(6), 2681–2685. DOI: 10.1021/bi00834a066
3. Bailey, H.H. L-S,R-buthionine sulfoximine: Historical development and clinical issues. Chem. Biol. Interact. 1998, 111–112, 239–254. DOI: 10.1016/S0009-2797(97)00164-6
4. Rao, S.L.N.; Meister, A. In Vivo Formation of Methionine Sulfoximine Phosphate, a Protein-Bound Metabolite of Methionine Sulfoximine. Biochemistry 1972, 11(7), 1123–1127. DOI: 10.1021/bi00757a001
5. Reggelin, M.; Zur, C. Sulfoximines: Structures, properties and synthetic applications. Synthesis (Stuttg). 2000, 2000(1), 1–64. DOI: DOI: 10.1055/s-2000-6217
6. Park, S.J.; Buschmann, H.; Bolm, C. Bioactive sulfoximines: Syntheses and properties of Vioxx® analogs. Bioorg. Med. Chem. Lett. 2011, 21(16), 4888–4890. DOI: 10.1016/j.bmcl.2011.06.029
7. Johnson, C.R. The Utilization of Sulfoximines and Derivatives as Reagents for Organic Synthesis. Acc. Chem. Res. 1973, 6(10), 341–347. DOI: 10.1021/ar50070a003
8. Mäder, P.; Kattner, L. Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry. J. Med. Chem. 2020, 63, 14243–14275. DOI: 10.1021/acs.jmedchem.0c00960
9. Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a Medicinal Chemist’s Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery. Eur. J. Med. Chem. 2017, 126, 225–245. DOI: 10.1016/j.ejmech.2016.09.091
10. Borst, M.L.G.; Ouairy, C.M.J.; Fokkema, S.C.; Cecchi, A.; Kerckhoffs, J.M.C.A.; De Boer, V.L.; et al. Polycyclic Sulfoximines as New Scaffolds for Drug Discovery. ACS Comb. Sci. 2018, 20(6), 335–343. DOI: 10.1021/acscombsci.7b00150
11. Lücking, U. Neglected sulfur[vi] pharmacophores in drug discovery: Exploration of novel chemical space by the interplay of drug design and method development. Org. Chem. Front. 2019, 6(8), 1319–1324. DOI: 10.1039/C8QO01233D
12. Sirvent, J.A.; Lücking, U. Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates. ChemMedChem 2017, 12(7), 487–501. DOI: 10.1002/cmdc.201700044
13. Andresini, M.; Tota, A.; Degennaro, L.; Bull, J.A.; Luisi, R. Synthesis and Transformations of NH-Sulfoximines. Chem. Eur. J. 2021, 27(69), 17293–17321. DOI: 10.1002/chem.202102619
14. O’Brien, P.; Phillips, D. W.; Towers, T. D. An azetidinium ion approach to 3-aryloxy-3-aryl-1-propanamines. Tetrahedron Lett. 2002, 43(41), 7333–7335. DOI: 10.1016/S0040-4039(02)01724-0
14. Tota, A.; Zenzola, M.; Chawner, S.J.; John-Campbell, S.S.; Carlucci, C.; Romanazzi, G.; et al. Synthesis of NH-sulfoximines from sulfides by chemoselective one-pot N- and O-transfers. Chem. Commun. (Camb) 2016, 53(2), 348–351. DOI: 10.1039/c6cc08891k
15. Bizet, V.; Hendriks, C.M.M.; Bolm, C. Sulfur imidations: Access to sulfimides and sulfoximines. Chem. Soc. Rev. 2015, 44(11), 3378–3390. DOI: 10.1039/C5CS00208G
16. Gais, H.J. Development of new methods for asymmetric synthesis based on sulfoximines. Heteroatom Chem. 2007, 18(5), 472–481. DOI: 10.1002/hc.20331
17. Okamura, H.; Bolm, C. Sulfoximines: Synthesis and catalytic applications. Chem. Lett. 2004, 33(5), 482–487. DOI: 10.1246/cl.2004.482
18. Lücking, U.; Kosemund, D.; Böhnke, N.; Lienau, P.; Siemeister, G.; Denner, K.; Bohlmann, R.; Briem, H.; Terebesi, I.; Bömer, U.; Schäfer, M.; Ince, S.; Mumberg, D.; Scholz, A.; Izumi, R.; Hwang, S.; von Nussbaum, F; Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer. J. Med. Chem. 2021, 64(15), 11651–1674. DOI: 10.1021/acs.jmedchem.1c01000
19. Han, Y.; Xing, K.; Zhang, J.; Tong, T.; Shi, Y.; Cao, H.; et al. Application of sulfoximines in medicinal chemistry from 2013 to 2020. Eur. J. Med. Chem. 2021, 209, Art. No: 112885. DOI: 10.1016/j.ejmech.2020.112885
20. Goldberg, F.W.; Kettle, J.G.; Xiong, J.; Lin, D. General synthetic strategies towards N-alkyl sulfoximine building blocks for medicinal chemistry and the use of dimethylsulfoximine as a versatile precursor. Tetrahedron 2014, 70(37), 6613–6622. DOI: 10.1016/j.tet.2014.06.120
21. Yano, K.; Shiotani, B. Emerging strategies for cancer therapy by ATR inhibitors. Cancer Sci. 2023, 114(7), 2709–2721. DOI: 10.1111/cas.15845
22. AstraZeneca; A Phase III, open-label, randomised, multicentre study of ceralasertib plus durvalumab versus docetaxel in patients with advanced or metastatic non-small cell lung cancer without actionable genomic alterations, and whose disease has progressed on or after prior anti PD (L)1 therapy and platinum based chemotherapy (LATIFY). ClinicalTrials.gov 2022. Available online: https://clinicaltrials.gov/study/NCT05450692 (accessed on 25.06.2025)
23. Bayer Aktiengesellschaft. Sulfoximine derivatives as CDK9 inhibitors. WO Patent WO2021143821A1, published 8 July 2021. Available online: https://patentimages.storage.googleapis.com/06/11/37/6bf766303dee6a/WO2021143821A1.pdf (accessed on 25.06.2025)
24. Lücking, U. Sulfoximines: A neglected opportunity in medicinal chemistry. Angew. Chem. Int. Ed. 2013, 52(36), 9399-9408. DOI: 10.1002/anie.201302209
25. Lücking, U. Sulfoximines in Medicinal Chemistry: Emerging Trends and Opportunities from the Drug Designer’s Perspective; published 18 May 2022; DOI: 10.26434/chemrxiv-2022-g58r5.
26. Walker, D.P.; Zawistoski, M.P.; McGlynn, M.A.; Li, J.C.; Kung, D.W.; Bonnette, P.C.; et al. Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 [PYK2] show reduced hERG activity. Bioorg. Med. Chem. Lett. 2009, 19(12), 3253–3258. DOI: 10.1016/j.bmcl.2009.04.093
27. Lu, D.; Vince, R. Discovery of potent HIV-1 protease inhibitors incorporating sulfoximine functionality. Bioorg. Med. Chem. Lett. 2007, 17(20), 5614–5619. DOI: 10.1016/j.bmcl.2007.07.095
28. Gnamm, C.; Jeanguenat, A.; Dutton, A.C.; Grimm, C.; Kloer, D.P.; Crossthwaite, A.J. Novel diamide insecticides: Sulfoximines, sulfonimidamides and other new sulfonimidoyl derivatives. Bioorg. Med. Chem. Lett. 2012, 22(11), 3800–3806. DOI: 10.1016/j.bmcl.2012.03.106
29. Aronson, J.K.; Ferner, R.E. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003, 327(7425), 1222–1225. DOI: 10.1136/bmj.327.7425.1222
30. Rothwell, P.M. External validity of randomised controlled trials: “To whom do the results of this trial apply?” Lancet 2005, 365(9453), 82–93. DOI: 10.1016/S0140-6736(04)17670-8
31. Edwards, I.R.; Aronson, J.K. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000, 356(9237), 1255–1259. DOI: 10.1016/S0140-6736(00)02799-9
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Michalina Skóra, Michał Nowacki, Maciej Dawidowski
This work is licensed under a Creative Commons Attribution 4.0 International License.
For all articles published in Prospects in Pharmaceutical Sciences copyright is retained by the authors. The journal publishes articles in the Open Access policy, within the CC BY 4.0 licence.
This is a human-readable summary of (and not a substitute for) the license. Disclaimer.
You are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material for any purpose, even commercially.
The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Notices:
You do not have to comply with the license for elements of the material in the public domain or where your use is permitted by an applicable exception or limitation.
No warranties are given. The license may not give you all of the permissions necessary for your intended use. For example, other rights such as publicity, privacy, or moral rights may limit how you use the material.
How to Cite
