A Review on the Natural Components Applied as Lead Compounds for Potential Multi-target Anti-AD Theranostic Agents.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects the health and quality of life of the elderly. Its pathogenesis is very complex and there is still a lack of effective clinical drugs to treat or control the development of AD. Studies have shown that ß-amyloid (Aß) deposition, tau protein hyperphosphorylation, reduced levels of brain cholinergic transmitters, and oxidative stress are the main causes of AD. Furthermore, recent studies showed that metal dyshomeostasis could relate to all the above pathogenesis of AD and was a key factor in the development of AD. Natural compounds and their derivatives have multi-target therapeutic effects on AD, and they also have the advantages of low toxicity, and low cost, which are important directions for anti- AD drugs. Meanwhile, early detection may play an important role in preventing the development of AD. The concept of "theranostic agent" combining molecular imaging probes and therapeutic drugs has emerged in recent years. Fluorescence imaging has been widely studied and applied because of its non-invasive, high resolution, high sensitivity, rapid imaging, and low cost. However, at present, most of the research methods in this field use individual therapeutic or diagnostic reagents, which is not conducive to exploring the optimal treatment time window and drug efficacy. Therefore, this work reviewed the natural compounds and their derivatives which all have been studied for both the in vitro and in vivo therapeutic and diagnostic anti-AD activities. At last, structure and activity relationship (SAR) was discussed and potential AD theranostic natural agents were put forwarded to provide a more detailed theoretical basis for the further development of drugs with diagnostic and therapeutic effects in AD.

Design, Synthesis, Calculation and Biological Activity Studies Based on Privileged Coumarin Derivatives as Multifunctional Anti-AD Lead Compound.

Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1-3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, ßamyloid (Aß) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico. Results showed that 1-3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aß aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC50 =11.15 µM). Compound 1-3 could also selectively chelate with Cu2+ and Al3+ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1-3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1-3 could be promising MTDLs applied as anti-AD candidate drugs.

A multifunctional metal regulator as the potential theranostic agent: Design, synthesis, anti-AD activities and metallic ion sensing properties.

Although there is no cure for Alzheimer's disease (AD) due to its complex pathogenesis, early detection and treatment can help delay the development of the disease. So, it is necessary to develop multifunctional metal regulators that can integrate the therapeutics and diagnostics effect against AD. In this work, N-(anthracene-9-ylmethylene)benzohydrazide (probe 1), a fluorescent probe with imine and carbonyl as chelating sites was designed and synthesized. Results showed that 1 had good activities related to AD, such as regulation of metal homeostasis, inhibition of ß-amyloid (Aß) aggregation and scavenging of reactive oxygen species. The selectivity experiment showed that probe 1 had a good recognition effect on Cu2+. Fluorescence imaging assay also indicated that probe 1 had a good fluorescence imaging effect on Cu2+ in living cells. Furthermore, probe 1 had showed no cytotoxicity and good BBB permeability. These results indicated that probe 1 had potential diagnostic and therapeutic capabilities, and can be used as the multifunctional theranostic agent for AD.