Discovery of Novel Imidazo[1,2-<i>a</i>]pyridine-Based HDAC6 Inhibitors as an Anticarcinogen with a Cardioprotective Effect

Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor <b>I-c4</b> containing imidazo[1,2-<i>a</i>]pyridine. Importantly, <b>I-c4</b> effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, <b>I-c4</b> could mitigate severe myocardial damage against H₂O₂ or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of <b>I-c4</b> was associated with reduction of inflammatory cytokines. Taken together, <b>I-c4</b> may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.