Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs

Abstract

During the last twenty years, organic fluorination chemistry established itself as an important tool to get a biologically active compound. This belief can be supported by the fact that every year, we are getting fluorinated drugs in the market in extremely significant numbers. Last year, also ten fluorinated drugs have been approved by FDA and during the COVID-19 pandemic, fluorinated drugs played a very crucial role to control the disease and saved many lives. In this review, we surveyed all ten fluorinated drugs approved by FDA in 2021 and all fluorinated drugs which were directly-indirectly used during the COVID-19 period, and emphasis has been given particularly to their synthesis, medicinal chemistry, and development process. Out of ten approved drugs, one drug pylarify, a radioactive diagnostic agent for cancer was approved for use in positron emission tomography imaging. Also, very briefly outlined the significance of fluorinated drugs through their physical, and chemical properties and their effect on drug development.

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants

“…However, its chiral center at the 3′ position is prone to racemization during synthesis, separation, and storage, resulting in unstable optical purity. Over the past two decades, fluorine substitution has emerged as one of the indispensable structural features in contemporary pharmaceuticals. − Around half of the most commercially successful drugs (blockbuster drugs) now incorporate fluorine atoms within their structures . The metabolic stability of compounds can be enhanced through the protection of metabolism-prone sites, including those susceptible to racemization and oxidative metabolism, via isosteric substitution of fluorine and hydrogen atoms .…”

The Role of Small Molecules Containing Fluorine Atoms in Medicine and Imaging Applications

“…Asciminib 5 is the active ingredient used in the treatment of CML containing a chiral compound with a difluorinated moiety [ 44 ]. CML is a disease associated with the overproduction of white blood cells in the bone marrow that arises from the BCR-ABL protein mutation leading to abnormal signaling pathways resulting in the growth and generation of leukemic cells [ 36 , 45 ]. These types of tyrosine kinase inhibitors work by binding to the ATP-binding site of BCR-ABL, thus transforming the disease into a controllable state during treatment [ 36 , 46 ].…”

“…CML is a disease associated with the overproduction of white blood cells in the bone marrow that arises from the BCR-ABL protein mutation leading to abnormal signaling pathways resulting in the growth and generation of leukemic cells [ 36 , 45 ]. These types of tyrosine kinase inhibitors work by binding to the ATP-binding site of BCR-ABL, thus transforming the disease into a controllable state during treatment [ 36 , 46 ]. The fluorine atoms in asciminib 5 interact with the carbonyl carbon of leucine-359 of the active site pocket, making the position of the fluorine atoms advantageous for improving the bioactivity of the overall compound [ 5 ].…”

Studies on the effect of fluorine on the interaction of different metal ions with a fluorinated azobenzene-Schiff base: intramolecular C–F activation under polar solvent

“…This is due to the inherent properties of the small-sized fluorine atom, which also has the highest electronegativity. The presence of fluorine atom per s in organic compounds has a dramatic effect on the structural and electronic properties of the overall molecule 1,2 and the resulting benefits have been extensively utilized in functional molecules 3 by incorporating fluorinated substituents at appropriate positions. Newer methods are being developed to incorporate F atoms into organic molecules for use as building blocks for a different purpose but the interconversion of fluorinated moieties into other functional groups is very challenging.…”