Substituting Superhalogens for the Fluorine Atom of 5‐Fluorouracil: A New Approach to Modulate its Structure, Electronic Properties, and Chemical Reactivity

The development of 5‐fluorouracil (5‐FU) analogs contributes to overcome its side effects and drug resistance. To explore more 5‐FU analogs, the substituent effect of BO 2 , NO 3 , and PO 3 on the geometric structure, electronic properties, and reactivity of 5‐FU has been systematically studied by density functional theory calculations and molecular docking in this article. It is revealed that the introduced superhalogens can not only form stable covalent bonds with the pyrimidine ring, like the original F atom in 5‐FU, but also pose significant effect on the geometric and electronic structures of 5‐FU. Even so, the obtained derivatives exhibit comparable chemical reactivity and binding affinity to thymidylate synthase as compared to 5‐FU. Moreover, as pseudo‐metabolites, these derivatives tend to form stable base pairs with adenine. In particular, the BO 2 ‐ and PO 3 ‐substituted derivatives both exhibit improved water and lipid solubility, which will benefits for their enhanced bioavailability. Therefore, these new 5‐FU derivatives show potential biological activity, providing valuable theoretical insights for the development of 5‐FU analogs.