Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design

Abstract

The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. In this context, fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule and temper inhibition of the hERG channel by basic amines. However, as a consequence of the unique properties of fluorine, it features prominently in the design of higher order structural metaphors that are more esoteric in their conception and which reflect a more sophisticated molecular construction that broadens biological mimesis. In this Perspective, applications of fluorine in the construction of bioisosteric elements designed to enhance the in vitro and in vivo properties of a molecule are summarized.

A Convenient Synthesis of Difluoroalkyl Ethers from Thionoesters Using Silver(I) Fluoride

“…Difluoroalkyl ethers are found in a variety of compounds ranging from liquid crystals (LCs) to pharmaceuticals and agrochemicals (Figure ). This highly polarized functional group has been shown to increase dielectric anisotropy and stability while broadening the nematic phase range of LCs, all of which are favorable application‐relevant properties .…”

“…This highly polarized functional group has been shown to increase dielectric anisotropy and stability while broadening the nematic phase range of LCs, all of which are favorable application‐relevant properties . In medicinal chemistry, difluoroalkyl ethers can enhance metabolic stability and impart unique conformational properties to molecules. For example, difluoroalkylaryl ethers have a small barrier to rotation around the ArO‐CF 2 R bond and can access perpendicular or “out of plane” conformers that are not readily adopted by the parent alkylaryl ethers .…”

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

“…effects. 33–39 For example, Pendergast et al 40 observed that a 2′-fluoro substitution of a benzo[ f ]quinazoline antifolate increased antitumor activity, which was attributed to the conformational restriction of the side-chain L-glutamate via a fluorine−hydrogen bond. 41 …”

Metallaphotoredox Difluoromethylation of Aryl Bromides

“…[1,2] While the implementation of the trifluoromethyl group (–CF 3 ) has been widely studied in medicinal chemistry, the relatively underexplored difluoromethyl group (–CF 2 H) has recently garnered significant attention by virtue of its capacity to serve as a lipophilic hydrogen bond donor and to act as a bioisostere for thiol and alcohol functionalities. [3,4] Modern approaches to the direct and selective introduction of the difluoromethyl group into aromatic rings typically rely on the metal-catalyzed cross-coupling of aryl electrophiles or nucleophiles with an appropriate CF 2 HR reagent, often designed for facile transmetallation or formal oxidative addition by the metal catalyst. [5,6] Given the pronounced practical significance of this emerging area, one of the greatest challenges is the rendering of readily available CF 2 H sources as effective difluoromethylating agents in cross-coupling.…”