1,5‐Disubstituted‐1,2,3‐triazoles as inhibitors of the mitochondrial Ca2+‐activated F1FO‐ATP(hydrol)ase and the permeability transition pore

The mitochondrial permeability transition pore (mPTP), a high‐conductance channel triggered by a sudden Ca2+ concentration increase, is composed of the F1FO‐ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5‐disubstituted 1,2,3‐triazole derivatives, five‐membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds 3a and 3b were selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+‐activated F1FO‐ATPase without affecting F‐ATPase activity sustained by the natural cofactor Mg2+. The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme–ATP complex. Both compounds show the same inhibition constant (Kʹi), but compound 3a has a doubled inactivation rate constant compared with compound 3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+‐activated F1FO‐ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP‐related diseases. Recently, triazole derivatives, obtained by replacing the isoxazole core in analog compounds have been considered as second‐generation inhibitors of the mitochondrial permeability transition pore (mPTP), a high‐conductance channel triggered by a sudden Ca2+ concentration increase, and involves the F1FO‐ATPase. In our study, the effects of two 1,5‐disubstituted 1,2,3‐triazole derivatives is investigated. The aim is to establish if these compounds, by interacting with the F1FO‐ATPase complex, can block mPTP formation and preserve Mg2+‐activated F1FO‐ATPase functionality.