Design and synthesis of 1,4,8-triazaspiro[4.5]decan-2-one derivatives as novel mitochondrial permeability transition pore inhibitors

Ischaemia/reperfusion injury (IRI) is a condition that occurs when tissues from different organs undergo reperfusion following an ischaemic event. The mitochondrial permeability transition pore (mPTP), a multiprotein platform including structural components of ATP Synthase with putative gate function, is an emerging pharmacological target that could be modulated to facilitate the restoration of organ function after a hypoxic insult. Herein, we reported the synthesis and biological characterisation of new molecules with a 1,4,8-triaza-spiro[4.5]decan-2-one framework of potential interest for the treatment of IRI able to inhibit the opening of mPTP in a cardiac model in vitro. Modelling studies were useful to rationalise the observed structure-activity relationship detecting a binding site for the investigated molecules at the interface between the c₈-ring and subunit a of ATP Synthase. Compound 14e was shown to display high potency as mPTP inhibitor combined with the capability to counteract cardiomyocytes death in an in vitro model of hypoxia/reoxygenation.