Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery.

There continues to be an exponential rise in the number of small molecule drugs that contain either a fluorine atom or a fluorinated fragment. While the unique properties of fluorine enable the precise modulation of a molecule's physicochemical properties, strategic bioisosteric replacement of fragments with fluorinated moieties represents an area of significant growth. This review discusses the strategic employment of fluorine substitution in the design and development of bioisosteres in medicinal chemistry. In addition, the classic exploitation of trifluoroethylamine group as an amide bioisostere is discussed. In each of the case studies presented, emphasis is placed on the context-dependent influence of the fluorinated fragment on the overall properties/binding of the compound of interest. Whereas utilization of bioisosteric replacements to modify molecular structures is commonplace within drug discovery, the overarching lesson to be learned is that the chances of success with this strategy significantly increase as the knowledge of the structure/environment of the biological target grows. Coupled to this, breakthroughs and learnings achieved using bioisosteres within a specific program are context-based, and though may be helpful in guiding future intuition, will not necessarily be directly translated to future programs. Another important point is to bear in mind what implications a structural change based on a bioisosteric replacement will have on the candidate molecule. Finally, the development of new methods and reagents for the controlled regioselective introduction of fluorine and fluorinated moieties into biologically relevant compounds particularly in drug discovery remains a contemporary challenge in organic chemistry.