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first fluoro-pharmaceutical, Florinef, to the latest fluoro-pharmaceuticals registered in 2019 and drugs that have been withdrawn.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.

Currently, more than 1,200 agrochemicals are listed and many of these are regularly used by farmers to generate the food supply to support the expanding global population. However, resistance to pesticides is an ever more frequently occurring phenomenon, and thus, a continuous supply of novel agrochemicals with high efficiency, selectivity, and low toxicity is required. Moreover, the demand for a more sustainable society, by reducing the risk chemicals pose to human health and by minimizing their environmental footprint, renders the development of novel agrochemicals an ever more challenging undertaking. In the last two decades, fluoro-chemicals have been associated with significant advances in the agrochemical development process. We herein analyze the contribution that organofluorine compounds make to the agrochemical industry. Our database covers 424 fluoro-agrochemicals and is subdivided into several categories including chemotypes, mode of action, heterocycles, and chirality. This in-depth analysis reveals the unique relationship between fluorine and agrochemicals.

The biosynthesis of penicillin and cephalosporin antibiotics in microorganisms requires the formation of the bicyclic nucleus of penicillin¹. Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the reaction of a tripeptide, δ-(L-α-aminoadipoyl)- L-cysteinyl-D-valine (ACV), and dioxygen to form isopenicillin N and two water molecules². Mechanistic studies suggest the reaction is initiated by ligation of the substrate thiolate to the iron centre, and proceeds through an enzyme-bound monocyclic intermediate³,⁴ (Fig. 1). Here we report the crystal structure of IPNS complexed to ferrous iron and ACV, determined to 1.3 å resolution. Based on the structure, we propose a mechanism for penicillin formation that involves ligation of ACV to the iron centre, creating a vacant iron coordination site into which dioxygen can bind. Subsequently, iron-dioxygen and iron-oxo species remove the requisite hydrogens from ACV without the direct assistance of protein residues (Fig. 2). The crystal structure of the complex with the dioxygen analogue, NO and ACV bound to the active-site iron supports this hypothesis.