Synthesis and pharmacological characterization of mitochondrial KATP channel openers with enhanced mitochondriotropic effects

• New mitochondria-targeting mitoKATP opener were synthesized. • TPP-conjugates are able to entry in the mitochondria to activate mitoK ATP channels. • Compounds 1–3 induce cardioprotection on oxidative stress-injured cardiomyoblasts. • Compound 1 has been tested on in vivo infarct model. • Compound 1 produces cardioprotective effect like the native mitoKATP channel opener. Mitochondria play a key role for deciding fate of cells and thus are considered an attractive target for pharmacological interventions focused on containment of myocardial ischemia/reperfusion (I/R) injury. Notably, the activation of mitochondrial potassium (mitoK) channels produces a mild depolarization of mitochondrial membrane, that contributes to reduce the driving force to calcium uptake and prevents the formation of mitochondrial transition membrane pore (MPTP); these events underlie anti-ischemic cardioprotection. However, an ideal mitoK channel opener should possess the fundamental requirement to be delivered at mitochondrial level; therefore, to improve the mitochondrial delivery of a previously characterized spirocyclic benzopyrane F81, new compounds have been developed. The three original triphenylphosphonium (TPP + )-derivatives of F81 ( 1 – 3 ), were evaluated for their cardioprotective activity on both isolated cardiac mitochondria and cardiac H9c2 cell line. Compound 1 was further investigated in an in vivo infarct model. This work confirms that the TPP + strategy applied to mitoKATP openers could foster mitochondrial delivery and enhance the cardioprotective effects of mitochondrial activators of potassium channels.