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

• DOI: 10.1111/nyas.14474
• Publication Date: 2020-09-22T12:24:50Z
• Authors: Vincenzo Algieri; Cristina Algieri; Loredana Maiuolo; Antonio De Nino; Alessandra Paglia...; Matteo Antonio Ta...; Fabiana Trombetti; Salvatore Nesci
• Keywords: MPTP

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