Design, Synthesis, and Pharmacological Evaluation of First‐in‐Class Multitarget N‐Acylhydrazone Derivatives as Selective HDAC6/8 and PI3Kα Inhibitors

Targeting histone deacetylases (HDACs) and phosphatidylinositol 3‐kinases (PI3Ks) is a very promising approach for cancer treatment. This manuscript describes the design, synthesis, in vitro pharmacological profile, and molecular modeling of a novel class of N‐acylhydrazone (NAH) derivatives that act as HDAC6/8 and PI3Kα dual inhibitors. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3/K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and inhibit PI3Kα show potential for the treatment of cancer. Surprising selectivity: A novel class of N‐acylhydrazone (NAH) derivatives that act as dual HDAC6/8 and PI3Kα inhibitors is described. The surprising selectivity for PI3Kα may be related to differences in the conformation in the active site. Cellular studies showed that these compounds act in HDAC6 inhibition and the PI3K/AKT/mTOR pathway. The compounds that are selective for inhibition of HDAC6/8 and PI3Kα show potential for the treatment of cancer.