Contribution of Organofluorine Compounds to Pharmaceuticals
Open accessAbstract
Inspired by the success of fluorinated corticosteroids in the 1950s and fluoroquinolones in the 1980s, fluorine-containing pharmaceuticals, which are also known as fluoro-pharmaceuticals, have been attracting attention for more than half of a century. Presently, about 20% of the commercial pharmaceuticals are fluoro-pharmaceuticals. In this mini-review, we analyze the prevalence of fluoro-pharmaceuticals in the market and categorize them into several groups based on the chemotype of the fluoro-functional groups, their therapeutic purpose, and the presence of heterocycles and/or chirality to highlight the structural motifs, patterns, and promising trends in fluorine-based drug design. Our database contains 340 fluoro-pharmaceuticals, from the first fluoro-pharmaceutical, Florinef, to the latest fluoro-pharmaceuticals registered in 2019 and drugs that have been withdrawn. The names and chemical structures of all the 340 fluorinated drugs discussed are provided in the Supporting Information.
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Adding a -CF3 moiety can reduce biological degradation, increase biological activity, and assist membrane transport, making the parent compound longer lasting or more effective.
“Addition of the -CF3 moiety can reduce biological degradation, increase biological activity, and assist with membrane transport, making the parent compound longer lasting or more effective”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [12]
“Fluoro-Pharmaceuticals in the Past Three Decades” (page not supplied) says C–F bonds often increase metabolic stability, supporting the reduced-degradation part in general. It describes effects on absorption as complex and does not establish that adding a –CF3 group assists membrane transport or increases biological activity relative to the parent compound. The potency example in “Chiral Fluoro-Pharmaceuticals” compares two fluorinated enantiomers, not a –CF3-modified compound with its parent. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSide-chain fluorinated aromatics are produced and used annually in unknown but likely considerable amounts.
“with unknown, but likely considerable amounts being produced and used annually (e.g., prozac).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [12]
The Chemotypes of the Fluoro-Pharmaceuticals on the Market section identifies 54 aryl–CF3 pharmaceuticals, supporting the presence of side-chain-fluorinated aromatics among marketed drugs. But the paper counts registered drugs, not amounts produced or used annually; searches for production quantities and Prozac did not establish that part of the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredMany side-chain fluorinated aromatics are used in pharmaceutical or agricultural applications.
“thus, many side-chain fluorinated aromatics are used in pharmaceutical (12) or agricultural (11) applications.”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [12]
The 2021 OECD revised definition of PFAS is more inclusive and unambiguously includes side-chain fluorinated aromatics.
“This revised definition is more inclusive with unambiguous inclusion of PFAS such as side-chain fluorinated aromatics (Fig. 2) (11, 12).”
From Per- and polyfluoroalkyl substances in the environment (2022) · cites this paper as [12]
The Chemotypes of the Fluoro-Pharmaceuticals on the Market section (page unavailable) classifies fluorinated drug structures, including aryl–CF3 compounds, but does not discuss PFAS definitions. Searches for the 2021 OECD revision and side-chain fluorinated aromatics found no passage addressing whether that definition includes them. (LLM, conf=0.78)
Experimental — accuracy not yet measuredAs of 2020, the number of pharmaceuticals containing fluorine atom(s) was 369, and in 2021, 13 new products containing fluorine were added; of these, 77 contain C-CF3 moieties.
“As of 2020, the number of pharmaceuticals containing fluorine atom(s) was 369 [247] and in 2021, 13 new products containing fluorine were added [248]. Of these, 77 contain C–CF3 moieties [from Fig. 4 in [247]].”
From Changes in tropospheric air quality related to the protection of stratospheric ozone in a changing climate (2023) · cites this paper as [247]
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Cites
Fluorine in medicinal chemistry
Purser, S., Moore, P. R., Swallow, S., & Gouverneur, V. (2007) · Chemical Society Reviews · doi:10.1039/b610213c · Cited by 7,616 · see citing works
Vitaku, E., Smith, D. T., & Njardarson, J. T. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501100b · Cited by 6,440 · see citing works
Wang, J., Sánchez‐Roselló, M., Aceña, J. L., del Pozo, C., Sorochinsky, A. E., Fustero, S., Soloshonok, V. A., & Liu, H. S. (2013) · Chemical Reviews · doi:10.1021/cr4002879 · Cited by 4,872 · see citing works
Applications of Fluorine in Medicinal Chemistry
Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J., & Meanwell, N. A. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00258 · Cited by 3,692 · see citing works
The Medicinal Chemist’s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
Roughley, S. D., & Jordan, A. M. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm200187y · Cited by 2,740 · see citing works
Ilardi, E. A., Vitaku, E., & Njardarson, J. T. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401375q · Cited by 1,626 · see citing works
Fluorine in medicinal chemistry: A review of anti-cancer agents
Isanbor, C., & O’Hagan, D. (2006) · Journal of Fluorine Chemistry · doi:10.1016/j.jfluchem.2006.01.011 · Cited by 1,125 · see citing works
Xu, X., Matsuzaki, K., & Shibata, N. (2014) · Chemical Reviews · doi:10.1021/cr500193b · Cited by 1,077 · see citing works
Self-citationModern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications
Kirsch, P. (2013) · doi:10.1002/9783527651351 · Cited by 1,029 · see citing works
Development trends for human monoclonal antibody therapeutics
Nelson, A. L., Dhimolea, E., & Reichert, J. M. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3229 · Cited by 1,027 · see citing works
The Significance of Chirality in Drug Design and Development
Brooks, W. H., Guida, W. C., & Daniel, K. G. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795165098 · Cited by 697 · see citing works
Zhu, Y., Han, J., Wang, J., Shibata, N., Sodeoka, M., Soloshonok, V. A., Coelho, J. A. S., & Toste, F. D. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00778 · Cited by 644 · see citing works
Self-citationFluorine‐Containing Drugs Approved by the FDA in 2018
Mei, H., Han, J., Fustero, S., Medio‐Simón, M., Sedgwick, D. M., Santi, C., Ruzziconi, R., & Soloshonok, V. A. (2019) · Chemistry - A European Journal · doi:10.1002/chem.201901840 · Cited by 461 · see citing works
Delost, M. D., Smith, D. T., Anderson, B. J., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00876 · Cited by 415 · see citing works
Recent Developments on the Trifluoromethylation of (Hetero)Arenes
Wu, X., Neumann, H., & Beller, M. (2012) · Chemistry - An Asian Journal · doi:10.1002/asia.201200211 · Cited by 366 · see citing works
Recent advances in enantioselective trifluoromethylation reactions
Shibata, N., Mizuta, S., & Kawai, H. (2008) · Tetrahedron Asymmetry · doi:10.1016/j.tetasy.2008.11.011 · Cited by 348 · see citing works
Self-citationPreparation and Utility of Organic Pentafluorosulfanyl-Containing Compounds
Savoie, P. R., & Welch, J. T. (2014) · Chemical Reviews · doi:10.1021/cr500336u · Cited by 342 · see citing works
THALIDOMIDE AND CONGENITAL ABNORMALITIES
Burley, D. M., & Lenz, W. (1962) · The Lancet · doi:10.1016/s0140-6736(62)91217-5 · Cited by 325 · see citing works
Heterocyclic Chemistry in Drug Discovery
Li, J. J. (2013) · Cited by 325 · see citing works
A Survey of the Structures of US FDA Approved Combination Drugs
Das, P., Delost, M. D., Qureshi, M. H., Smith, D. T., & Njardarson, J. T. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01610 · Cited by 314 · see citing works
Chiral pharmaceuticals: A review on their environmental occurrence and fate processes
Sanganyado, E., Lu, Z., Fu, Q., Schlenk, D., & Gan, J. J. (2017) · Water Research · doi:10.1016/j.watres.2017.08.003 · Cited by 295 · see citing works
Fluorine in Medicinal Chemistry
Swallow, S. (2015) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2014.11.001 · Cited by 280 · see citing works
The fluorinated natural products
Harper, D. B., & O’Hagan, D. (1994) · Natural Product Reports · doi:10.1039/np9941100123 · Cited by 279 · see citing works
(2011) · Wiley eBooks · doi:10.1002/9781118075647 · Cited by 243 · see citing works
New entries toward the synthesis of OCF 3 -containing molecules
Besset, T., Jubault, P., Pannecoucke, X., & Poisson, T. (2016) · Organic Chemistry Frontiers · doi:10.1039/c6qo00164e · Cited by 195 · see citing works
Tokunaga, E., Yamamoto, T., Ito, E., & Shibata, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-35457-6 · Cited by 171 · see citing works
Self-citationShibata, N., Ishimaru, T., Nakamura, S., & Toru, T. (2007) · Journal of Fluorine Chemistry · doi:10.1016/j.jfluchem.2006.12.014 · Cited by 167 · see citing works
Self-citationCatalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a CCF3 Stereogenic Center
Huang, Y., Yang, X., Chen, Z., Verpoort, F., & Shibata, N. (2015) · Chemistry - A European Journal · doi:10.1002/chem.201500361 · Cited by 141 · see citing works
Self-citationStructural basis of thalidomide enantiomer binding to cereblon
Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H., & Hakoshima, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-19202-7 · Cited by 131 · see citing works
Self-citationTransforming Computational Drug Discovery with Machine Learning and AI
Smith, J. S., Roitberg, A. E., & Isayev, O. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00437 · Cited by 109 · see citing works
Das, P., Tokunaga, E., & Shibata, N. (2017) · Tetrahedron Letters · doi:10.1016/j.tetlet.2017.11.015 · Cited by 80 · see citing works
Self-citationBioactive Heterocyclic Compound Classes
(2012) · Wiley eBooks · doi:10.1002/9783527664450 · Cited by 72 · see citing works
Synthesis of Trifluoromethyl Pyrroles and Their Benzo Analogues
Haufe, G., Nenajdenko, V. G., Muzalevskiy, V. M., Shastin, A. V., & Balenkova, E. S. (2009) · Synthesis · doi:10.1055/s-0029-1217080 · Cited by 50 · see citing works
Tokunaga, E., Akiyama, H., Soloshonok, V. A., Inoue, Y., Hara, H., & Shibata, N. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182152 · Cited by 35 · see citing works
Self-citationIntroduction to Biological and Small Molecule Drug Research and Development: Theory and Case Studies
Laird, T. (2013) · Organic Process Research & Development · doi:10.1021/op400230q · Cited by 34 · see citing works
Small Molecule Medicinal Chemistry
(2015) · Wiley eBooks · doi:10.1002/9781118771723 · Cited by 22 · see citing works
The story of SF5-substituted pyridines
Cui, B., & Shibata, N. (2019) · Phosphorus, sulfur, and silicon and the related elements · doi:10.1080/10426507.2019.1602624 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- a Murakami H. Sekai-no Shinyaku 1991–2000; CMC Publishing Co., Ltd.: Tokyo, Japan, 2002. b O’Neil M. J., Ed. The Merck Index 14th ed.; Merck & Co., Inc.: Whitehouse Station, NJ, USA, 2006. c Murakami H. Sekai-no Shinyaku 2010. In Gekkan Fine Chemical; CMC Publishing Co., Ltd.: Tokyo, Japan, 2011; Vol. 40, pp 70– 80. d Bronson J.; Black A.; Dhar T. G. M.; Ellswroth B. A.; Merritt J. R. Ch. 27-To Market, to Market-2013. In Annu. Rep. Med. Chem.; Academic Press Inc.: London, UK, 2014; Vol. 49, pp 437– 508.
- Fluorine in Heterocyclic Chemistry Vols. 1 & 2; Nenajdenko V., Ed.; Springer Cham: Heidelberg, 2014.
Cited by
Sorted by citations
Per- and polyfluoroalkyl substances in the environment
Evich, M. G., Davis, M. J. B., McCord, J. P., Acrey, B., Awkerman, J. A., Knappe, D. R. U., Lindstrom, A. B., Speth, T. F., Tebes-Stevens, C., Strynar, M. J., et al. (2022) · Science · doi:10.1126/science.abg9065 · Cited by 2,157 · see citing works
“2) (11, 12).”
Current Contributions of Organofluorine Compounds to the Agrochemical Industry
Ogawa, Y., Tokunaga, E., Kobayashi, O., Hirai, K., & Shibata, N. (2020) · iScience · doi:10.1016/j.isci.2020.101467 · Cited by 1,253 · see citing works
Self-citationFluorine-containing pharmaceuticals approved by the FDA in 2020: Synthesis and biological activity
Yu, Y., Liu, A., Dhawan, G., Mei, H., Zhang, W., Izawa, K., Soloshonok, V. A., & Han, J. (2021) · Chinese Chemical Letters · doi:10.1016/j.cclet.2021.05.042 · Cited by 182 · see citing works
Insufficient evidence for the existence of natural trifluoroacetic acid
Joudan, S., De Silva, A. O., & Young, C. J. (2021) · Environmental Science: Processes & Impacts · doi:10.1039/d1em00306b · Cited by 84 · see citing works
Madronich, S., Sulzberger, B., Longstreth, J. D., Schikowski, T., Andersen, M. P. S., Solomon, K. R., & Wilson, S. R. (2023) · Photochemical & Photobiological Sciences · doi:10.1007/s43630-023-00369-6 · Cited by 64 · see citing works
Dekant, W., & Dekant, R. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03454-y · Cited by 55 · see citing works
Finding Fluorine: Photoproduct Formation during the Photolysis of Fluorinated Pesticides
Bhat, A. P., Pomerantz, W. C. K., & Arnold, W. A. (2022) · Environmental Science & Technology · doi:10.1021/acs.est.2c04242 · Cited by 49 · see citing works
Ortbal, S. K., Masud, M. A. A., Kebede, M. M., Rak, A., & Terry, L. G. (2026) · ACS ES&T Water · doi:10.1021/acsestwater.6c00546
- Authors
- Inoue, M., Sumii, Y., & Shibata, N.
- Affiliations
- Sagami Chemical Research Institute (JP)
- Nagoya Institute of Technology (JP)
- Zhejiang Normal University (CN)
- Corresponding author
- Inoue, Munenori
- Shibata, Norio
- Venue
- ACS Omega
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-04-22
- Volume
- 5
- Issue
- 19
- Pages
- 10633-10640
- ISSN
- 2470-1343 (ISSN-L)
- PMC
- PMC7240833
- OpenAlex
- W3019266968
- Semantic Scholar
- d2f777e9375d53d2baa4cf6c521e65f1d6a29168
- Cited by
- 1,944
- References
- 37
- Citations by year
- 2026: 276 · 2025: 389 · 2024: 384 · 2023: 359 · 2022: 301 · 2021: 200 · 2020: 35
- FWCI
- 19.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- ACS Omega (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (JP 18H02553, JP 18H04401)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Fluorine in Organic Chemistry
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Organophosphorus compounds synthesis
- Keywords
- fluorinated drugs, organofluorine compounds, fluorinated corticosteroids, fluoroquinolones, heterocyclic compounds, chirality, structural motifs, drug withdrawal
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