Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule

Metal-ion misregulation and
oxidative stress continue to be components of the continually evolving
hypothesis describing the molecular origins of Alzheimer’s
disease. Therefore, these features are viable targets for synthetic
chemists to explore through hybridizations of metal-binding ligands
and antioxidant units. To date, the metal-binding unit in potential
therapeutic small molecules has largely been inspired by clioquinol
with the exception of a handful of heterocyclic small molecules and
open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane)
have the advantage of straightforward N-based modifications, allowing
the addition of functional groups. In this work, we report the synthesis
of a triazine bridged system containing two cyclen metal-binding units
and an antioxidant coumarin appendage inspired by nature. This new
potential therapeutic molecule shows the ability to bind copper in
a unique manner compared to other chelates proposed to treat Alzheimer’s
disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di­(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)­amino)­ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show
that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC50 = 80 μM)
and the ability to protect HT-22 neuronal cells from cell death induced
by Aβ + copper­(II), thus demonstrating the potential for molecule 1 to serve as a multimodal therapeutic for Alzheimer’s
disease.