Principles and Applications of CF2X Moieties as Unconventional Halogen Bond Donors in Medicinal Chemistry, Chemical Biology, and Drug Discovery

As an orthogonal principle to the established (hetero)arylhalides,we herein highlight the usefulness of CF2X (X = Cl, Br,or I) moieties. Using tool compounds bearing CF2X moieties,we study their chemical/metabolic stability and their logP/solubility,as well as the role of XB in their small molecular crystal structures.Employing QM techniques, we analyze the observed interactions, provideinsights into the conformational flexibilities and preferences inthe potential interaction space. For their application in moleculardesign, we characterize their XB donor capacities and its interactionstrength dependent on geometric parameters. Implementation of CF2X acetamides into our HEFLibs and biophysical evaluation (STD-NMR/ITC),followed by X-ray analysis, reveals a highly interesting binding modefor fragment 23 in JNK3, featuring an XB of CF2Br toward the P-loop, as well as chalcogen bonds. We suggest thatunderexplored chemical space combined with unconventional bindingmodes provides excellent opportunities for patentable chemotypes fortherapeutic intervention.

Automated summary

This article highlights the usefulness of CF2X (X = Cl, Br, or I) moieties as an orthogonal principle to the established (hetero)arylhalides. The chemical/metabolic stability, logP/solubility, and crystal structures of compounds bearing CF2X groups are studied. The interactions, conformational flexibilities, and XB donor capacities of CF2X moieties are analyzed. Furthermore, the implementation of CF2X acetamides in molecular design and their binding modes in JNK3 are investigated.