Discovery of novel harmine derivatives as GSK‐3β/DYRK1A dual inhibitors for Alzheimer's disease treatment

Abstract Multitarget‐directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase‐3β (GSK‐3β) and dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK‐3β and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK‐3β and DYRK1A in vitro. ZLQH‐5 was selected as the best compound due to the most potent inhibitory effect against GSK‐3β and DYRK1A. Molecular docking studies demonstrated that ZLQH‐5 could form stable interactions with the ATP binding pocket of GSK‐3β and DYRK1A. In addition, ZLQH‐5 showed low cytotoxicity against SH‐SY5Y and HL‐7702, good blood–brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH‐5 also attenuated the tau hyperphosphorylation in the okadaic acid SH‐SY5Y cell model. These results indicated that ZLQH‐5 could be a promising dual‐target drug candidate for the treatment of AD.