Compound 19(Alma Mater Studiorum-University of Bologna)

Alzheimer's disease (AD), the most common type of dementia, currently represents an unmet medical need worldwide. It is considered the result of a systemic breakdown of multiple physiological networks which might be adequately tackled by multitarget drugs (MTDs) aimed at restoring the perturbed networks. Accumulating evidence suggests that Glycogen Synthase Kinase 3β (GSK-3β) and Histone Deacetylases (HDACs) synergistically contribute to disease pathogenesis. In a continuation of our efforts to develop MTDs for AD, we manipulated the structure of a previously reported GSK-3β inhibitor, AR-A014418, to develop a new class of dual GSK-3β/HDACs binding agents. Among the 34 synthesized derivatives, compound 19 showed encouraging results, inhibiting GSK-3β (IC₅₀ = 0.04 ± 0.01 μM) HDAC2 (IC₅₀ = 1.05 ± 0.11 μM), and HDAC6 (IC₅₀ = 1.52 ± 0.06 μM). In addition, compound 19 inhibits HDAC2 and 6 activities in cells and blocks tau hyperphosphorylation. Interestingly, it is nontoxic in SH-SY5Y cells up to 100 μM, and exerts neuroprotective effects. Moreover, to better elucidate the mode of action of compound 19, its effects on the molecular pathways of SH-SY5Y cells were studied using a proteome-wide analysis. We uncovered the potential of compound 19, which represents a promising hit for the development of innovative disease-modifying agents.