Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-β aggregation for the treatment of Alzheimer's disease

Abstract A series of coumarin-pargyline hybrids ( 4a-x ) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid- β (A β ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC 50 , 0.027 ± 0.004  μ M for MAO-B; 3.275 ± 0.040  μ M for MAO-A) and A β 1-42 aggregation (54.0 ± 1.1%, 25  μ M). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.