HDAC1/MAO-B dual inhibitors against Alzheimer’s disease: Design, synthesis and biological evaluation of N-propargylamine-hydroxamic acid/o-aminobenzamide hybrids

A series of N -propargylamine-hydroxamic acid/ o -aminobenzamide hybrids inhibitors combining the typical pharmacophores of hydroxamic acid/o-aminobenzamide and propargylamine were designed and synthesized as HDAC1/MAO-B dual inhibitors for the treatment of Alzheimer’s disease. Most of the hybrids displayed moderate to good MAO-B inhibitory activities. Among them, Hybrid If exhibited the most potent activity against MAO-B and HDAC1 (MAO-B, IC 50  = 99.0 nM; HDAC1, IC 50  = 21.4 nM) and excellent MAO selectively (MAO-A, IC 50  = 9923.0 nM; SI = 100.2). Moreover, compound If significantly reversed Aβ1-42-induced PC12 cell damage and decreased the production of intracellular ROS, exhibiting favorable antioxidant activity. More importantly, hybrid If instantly penetrated the BBB and accumulated in brain tissue as well as markedly ameliorated cognitive dysfunction in a Morris water maze ICR mice model. In summary, HDAC1/MAO-B dual inhibitor If is a promising potential agent for the therapy of Alzheimer’s disease.