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)­aryl halides, 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, provide insights into the conformational flexibilities and preferences in the potential interaction space. For their application in molecular design, we characterize their XB donor capacities and its interaction strength 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 mode for fragment 23 in JNK3, featuring an XB of CF2Br toward the P-loop, as well as chalcogen bonds. We suggest that underexplored chemical space combined with unconventional binding modes provides excellent opportunities for patentable chemotypes for therapeutic intervention.相较于已成熟应用的（杂）芳基卤化物类正交策略，本文着重阐述CF₂X（X=Cl、Br或I）基团的应用价值。我们借助携带CF₂X基团的工具化合物，系统研究其化学稳定性、代谢稳定性、油水分配系数（logP）与溶解度，并探究XB（卤键）在其小分子晶体结构中的作用机制。我们采用QM（量子力学）技术对观测到的相互作用进行分析，深入阐释潜在相互作用空间内的构象柔性与构象偏好。针对其在分子设计中的应用场景，我们表征了该类基团的XB供体能力，以及其相互作用强度随几何参数变化的依赖规律。将CF₂X取代乙酰胺引入我们的HEFLibs文库后，开展生物物理评价（STD-NMR（饱和转移差谱核磁共振）、ITC（等温滴定量热法）），并辅以X射线晶体学分析，结果显示片段23在JNK3中呈现出极具研究价值的结合模式：CF₂Br与P环形成XB，同时伴随硫族键相互作用。我们认为，未被充分探索的化学空间结合非常规结合模式，可为可申请专利的治疗用化学型提供极佳的开发机遇。