Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a <i>Drosophila</i> Model of Alzheimer’s Disease

Alzheimer’s disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-β (Aβ) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-Aβ clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual Aβ and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells overexpressing Aβ₄₂ and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood–brain barrier (BBB), together with the <i>in vitro</i> interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds <b>22</b> and <b>23</b> were tested <i>in vivo</i>, in a Drosophila melanogaster model of AD. The carbazole derivative <b>22</b> (20 μM) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of Aβ₄₂ expressing flies and generating a better outcome than doxycycline (50 μM). Moreover, <b>22</b> proved to be able to decrease Aβ₄₂ aggregates in the brains of the flies. We conclude that bivalent small molecules based on <b>22</b> deserve further attention as hits for dual Aβ/Tau aggregation inhibition in AD.