Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Fluorine in Pharmaceuticals: Looking Beyond Intuition.

The Lancet Commission on pollution and health

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

Applications of Fluorine in Medicinal Chemistry

Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas Yu Zhou,† Jiang Wang,† Zhanni Gu,† Shuni Wang,† Wei Zhu,† Jose ́ Luis Aceña,*,‡,§ Vadim A. Soloshonok,*,‡,∥ Kunisuke Izawa,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastiań, Spain Department of Organic Chemistry, Autońoma University of Madrid, Cantoblanco, 28049 Madrid, Spain IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, Japan 533-0024

Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas

In recent years, neonicotinoid insecticides have been the fastest growing class of insecticides in modern crop protection, with widespread use against a broad spectrum of sucking and certain chewing pests. As potent agonists, they act selectively on insect nicotinic acetylcholine receptors (nAChRs), their molecular target site. The discovery of neonicotinoids can be considered as a milestone in insecticide research and greatly facilitates the understanding of functional properties of the insect nAChRs. In this context, the crystal structure of the acetylcholine-binding proteins provides the theoretical foundation for designing homology models of the corresponding receptor ligand binding domains within the nAChRs, a useful basis for virtual screening of chemical libraries and rational design of novel insecticides acting on these practically relevant channels. Because of the relatively low risk for nontarget organisms and the environment, the high target specificity of neonicotinoid insecticides, and their ...

Overview of the Status and Global Strategy for Neonicotinoids

The task of inventing and developing active ingredients with useful biological activities requires a search for novel chemical substructures. This process may trigger the discovery of whole classes of chemicals of potential commercial interest. Similar biological effects can often be achieved by completely different compounds. However, compounds within a given structural family may exhibit quite different biological activities depending on their interactions with different intracellular proteins like enzymes or receptors. By varying the functional groups and structural elements of a lead compound, its interaction with the active site of the target protein, as well as its physicochemical, pharmacokinetic, and dynamic properties can be improved. In this context, the introduction of fluorine into active ingredients has become an important concept in the quest for a modern crop protection product with optimal efficacy, environmental safety, user friendliness, and economic viability. Fluorinated organic compounds represent an important and growing family of commercial agrochemicals. A number of recently developed agrochemical candidates represent novel classes of chemical compounds with new modes of action; several of these compounds contain new fluorinated substituents. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of fluorine can lead to either an increase or a decrease in the efficacy of a compound depending on its changed mode of action, physicochemical properties, target interaction, or metabolic susceptibility and transformation. Therefore, it is still difficult to predict the sites in a molecule at which fluorine substitution will result in optimal desired effects.

The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop Protection

In recent years, neonicotinoids have been the fastest-growing class of insecticides in modern crop protection, with widespread use against a broad spectrum of sucking and certain chewing pests As potent agonists, they act selectively on insect nicotinic acetylcholine receptors, their molecular target site The discovery of neonicotinoids can be considered as a milestone in insecticide research and facilitates greatly the understanding of the functional properties of insect nicotinic acetylcholine receptors Because of the relatively low risk for non-target organisms and environment, the high target specificity of neonicotinoid insecticides and their versatility in application methods, this important class has to be maintained globally for integrated pest management strategies and insect resistance management programmes This review comprehensively describes particularly the origin, structure and bonding as well as associated properties of neonicotinoid insecticides

Neonicotinoids—from zero to hero in insecticide chemistry

Alpha-fluorinated ethers, thioethers, and amines: anomerically biased species.

The past 30 years have witnessed a period of significant expansion in the use of halogenated compounds in the field of agrochemical research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochemical with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, especially in synthetic methods for particular halogen-substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the number of commercial products containing 'mixed' halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine-substituted agrochemicals throughout the twenty-first century. A number of these recently developed agrochemical candidates containing halogen substituents represent novel classes of chemical compounds with new modes of action. However, the complex structure-activity relationships associated with biologically active molecules mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compound, depending on its changed mode of action, physicochemical properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a molecule at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilisation of halogens and their unique role in the design of modern agrochemicals, exemplified by various commercial products from Bayer CropScience coming from different agrochemical areas.

Peter Jeschke

Papers

Overview of the Status and Global Strategy for Neonicotinoids

The Unique Role of Fluorine in the Design of Active Ingredients for Modern Crop Protection

Neonicotinoids—from zero to hero in insecticide chemistry

Alpha-fluorinated ethers, thioethers, and amines: anomerically biased species.

The unique role of halogen substituents in the design of modern agrochemicals.