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.