Resveratrol-Based MTDLs to Stimulate Defensive and Regenerative Pathways and Block Early Events in Neurodegenerative Cascades

By replacing a phenolic
ring of (E)-resveratrol
with an 1,3,4-oxadiazol-2­(3H)-one heterocycle, new
resveratrol-based multitarget-directed ligands (MTDLs) were obtained.
They were evaluated in several assays related to oxidative stress
and inflammation (monoamine oxidases, nuclear erythroid 2-related
factor, quinone reductase-2, and oxygen radical trapping) and then
in experiments of increasing complexity (neurogenic properties and
neuroprotection vs okadaic acid). 5-[(E)-2-(4-Methoxyphenyl)­ethenyl]-3-(prop-2-yn-1-yl)-1,3,4-oxadiazol-2­(3H)-one (4e) showed a well-balanced MTDL profile:
cellular activation of the NRF2-ARE pathway (CD = 9.83 μM),
selective inhibition of both hMAO-B and QR2 (IC50s = 8.05
and 0.57 μM), and the best ability to promote hippocampal neurogenesis.
It showed a good drug-like profile (positive in vitro central nervous
system permeability, good physiological solubility, no glutathione
conjugation, and lack of PAINS or Lipinski alerts) and exerted neuroprotective
and antioxidant actions in both acute and chronic Alzheimer models
using hippocampal tissues. Thus, 4e is an interesting
MTDL that could stimulate defensive and regenerative pathways and
block early events in neurodegenerative cascades.