Tacrine and melatonin are well-known drugs with activities as an acetylcholinesterase (AChE) inhibitor and free radical scavenger, respectively. In this work, we report new hybrids of both drugs that display higher in vitro properties than the sum of their parts. As selective inhibitors of human AChE, their IC(50) values range from sub-nanomolar to picomolar. They exhibit a higher oxygen radical absorbance capacity than does melatonin and are predicted to be able to cross the blood-brain barrier to reach their targets in the central nervous system.
By using fragments endowed with interesting and complementary
properties
for the treatment of Alzheimer’s disease (AD), a new family
of tacrine–4-oxo-4H-chromene hybrids has been
designed, synthesized, and evaluated biologically. The tacrine fragment
was selected for its inhibition of cholinesterases, and the flavonoid
scaffold derived from 4-oxo-4H -chromene was chosen
for its radical capture and β-secretase 1 (BACE-1) inhibitory
activities. At nano- and picomolar concentrations, the new tacrine–4-oxo-4H-chromene hybrids inhibit human acetyl- and butyrylcholinesterase
(h-AChE and h-BuChE), being more potent than the parent inhibitor,
tacrine. They are also potent inhibitors of human BACE-1, better than
the parent flavonoid, apigenin. They show interesting antioxidant
properties and could be able to penetrate into the CNS according to
the in vitro PAMPA-BBB assay. Among the hybrids investigated, 6-hydroxy-4-oxo- N-{10-[(1,2,3,4-tetrahydroacridin-9-yl)amino]decyl}-4 H-chromene-2-carboxamide (19) shows potent
combined inhibition of human BACE-1 and ChEs, as well as good antioxidant
and CNS-permeable properties.
Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.