Scaffold hopping for discovery of N, N-dibenzylcinnamamide (DBCA) derivatives as novel allosteric GSK-3β inhibitors: Design, synthesis and anti-inflammatory evaluation

Glycogen synthase kinase-3β (GSK-3β) has been identified to promote inflammation and its inhibitors have also been proven to treat some inflammatory-mediated diseases in animal models. Allosteric inhibitors inherently have better therapeutical value due to their higher specificity than ATP-competitive ones. In this paper, we reported the discovery of a novel series of N, N-dibenzylcinnamamide (DBCA) compounds as allosteric GSK-3β inhibitors via a scaffold hopping strategy. The in vitro enzymatic evaluation showed most DBCA derivatives have inhibitory effects on GSK-3β in a micromolar scale. Among them, seven compounds D-27 ∼ 33 showed activities at lower micromolar levels. Kinetic analysis revealed this type of compound inhibited GSK-3β by an allosteric modulation. The in vitro cytokine release assay demonstrated that D-33 could reduce the release of proinflammatory cytokines IL-1β and IL-6 while keeping IL-12 and TNF-α intact, indicating it might be a potential safer candidate for certain inflammatory conditions, such as neuroinflammatory diseases. Finally, docking studies were performed to suggest binding modes that explain the impacts of candidates on the enzyme.