Switchable Reactivity of Hydrazonoyl Halides: Enabling the Discovery of Potent Hypoxia-Inducible Factor Inhibitors

High Resolution Image Download MS PowerPoint Slide A substituent-regulated divergent cycloaddition reaction between hydrazonoyl halides and 2-aminochalcones has been developed. In this study, substituents effectively reversed the intrinsic reactivity of hydrazonoyl halides, marking the first instance where hydrazonoyl halides can function as C1 synthons─with the azomethine carbon displaying unprecedented nucleophilic reactivity, a property that deviates from the established paradigms of hydrazonoyl halide chemistry. The reaction mechanism underlying this methodology was verified via density functional theory calculations. Moreover, biological activity evaluations demonstrated that the synthesized indolines suppress hypoxia-inducible factor activity both in vitro and in vivo, indicating that these compounds are promising candidates for further development as potential anticancer agents.