A coumarin-based multifunctional chemosensor for Cu²⁺/Al³⁺ as an AD theranostic agent: Synthesis, X-ray single...

The pathogenesis of Alzheimer's disease (AD) is complex. So far there is no effective drug to treat the disease. The pathological changes of AD began 30 years before symptoms, so early diagnosis is considered to be important for AD treatment. Integrating diagnosis and therapy into a single regent has provided a new opportunity for AD treatment. Given that metal dyshomeostasis is thought to be one of the key factors to cause AD, a Schiff base substituted coumarin (probe 1) has been designed and synthesized as a selective metal chelator for multi-factor anti-AD in this work. The results of metal ions recognition showed that probe 1 had high selective fluorescent turn-on response to Al³⁺ and fluorescent turn-off response to Cu²⁺, due to intramolecular charge transfer (ICT) mechanism. Meanwhile, the results of both in vitro and in vivo bioactivities evaluation including metal chelation, reactive oxide species (ROS) elimination, self-/Cu²⁺-induced Aβ aggregation showed that 1 and 1-Cu(II) complex had excellent synergistic anti-AD activities. In addition, 1 had low cytotoxicity and was predicted to cross the blood-brain barrier (BBB). Noticeably, X-ray single crystal diffraction of 1-Cu(II) provided molecular level information to explain the structure and theranostic activity relationship. To sum up, 1 may be a promising candidate for the development of AD theranostic agent.