LAUSR

We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI‐34051 (HDAC8), which we recognized share the same N‐benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl‐indole and ‐indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK‐N‐BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI‐34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.