Review on Role of Fluorinated Scaffolds in Pharmaceutical Chemistry: Enhancing Drug Properties through Strategic Fluorination

Fluorine ions have transformed the manufacturing of modern medications and continue to dramatically change the physical, pharmacokinetic, and pharmacodynamic properties of drugs. The physical properties of carbon-fluorine bonds are unique due to the very high bond dissociation energy of this bond, and the fact that fluorine is a highly electronegative atom with minimal steric interference from bonding to a carbon atom, provide chemists with an opportunity to precisely modify the molecular properties of drugs without changing the overall framework of the molecule. Based on the above characteristics of C-F bonds, strategic fluorine incorporation into many biologically active molecules increases the molecules' lipophilicity, membrane permeability, metabolic stability, and resistance to enzymatic degradation, and therefore increases the bioavailability and half-life duration in vivo of those molecules. There is also a significant body of knowledge that demonstrates substituting fluorine atoms in drug molecules impacts the electronic distribution, conformation, and intermolecular interactions of those molecules, resulting in increased affinity and selectivity towards their intended targets. This review presents and discusses the influence of fluorine in drug design and highlights the influence of fluorine on molecular action via structural activity relationships as well as the method of synthesizing fluorinated drug molecules. Representative patient-indicated and commercially available fluorinated drug examples that have been clinically approved include fluoroquinolone antibiotics and fluorinated steroids used in the treatment of cancer, neurological, infectious, and cardiovascular diseases. The review additionally provides a discussion of emerging methodologies that utilize novel electrophilic and nucleophilic fluorination reagents, late stage fluorination strategies, and the incorporation of trifluoromethyl or perfluoroalkyl groups into drug structures for optimization of pharmacokinetic properties In summary, this review illustrates how the strategic fluorination is a key component of the expanded utility of chemical compounds to develop new drugs.