Zinc-porphyrin complex as multifunctional anti-AD agent: Synthesis, X-ray single crystal analysis and activity study

Area of Science:

• Neuroscience
• Materials Science
• Medicinal Chemistry

Background:

• Alzheimer's disease (AD) lacks effective treatments, with complex pathology involving metal dyshomeostasis.
• Zinc and copper imbalances, along with amyloid-beta (Aβ) aggregation and oxidative stress, contribute to neurodegeneration in AD.

Purpose of the Study:

• To design and synthesize novel compounds targeting multiple AD pathological pathways.
• To evaluate the therapeutic potential of a carbamate porphyrin derivative (1) and its zinc complex (1-Zn) against AD.

Main Methods:

• Synthesis and crystallographic analysis of compounds 1 and 1-Zn.
• Computational studies including Hirshfeld analysis, molecular dynamics, and frontier molecular orbital calculations.
• In vitro and in vivo assays for metal chelation, antioxidant activity, Aβ aggregation inhibition, and cholinesterase inhibition.

Main Results:

• Compound 1-Zn demonstrated dual-function metal regulation, chelating excess copper (Cu2+) and releasing zinc (Zn2+).
• Both compounds exhibited significant reactive oxygen species (ROS) scavenging and Aβ aggregation inhibition comparable to positive controls.
• 1-Zn showed cholinesterase inhibition activity similar to rivastigmine.

Conclusions:

• The novel carbamate porphyrin derivative (1) and its zinc complex (1-Zn) show potential as multi-target agents for Alzheimer's disease.
• These compounds warrant further investigation for clinical translation due to their promising therapeutic profile.