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

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

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2505907. doi: 10.1080/14756366.2025.2505907.
Valentina Albanese 1,  Gaia Pedriali 2,  Martina Fabbri 3,  Antonella Ciancetta 3,  Silvia Ravagli 3,  Chiara Roccatello 3,  Remo Guerrini 3 4,  Giampaolo Morciano 2 5 6,  Delia Preti 3,  Paolo Pinton 2 4 5,  Salvatore Pacifico 3
Affiliations

Affiliations

  • 1 Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy.
  • 2 Maria Cecilia Hospital, GVM Care & Research, Cotignola, Italy.
  • 3 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy.
  • 4 Technopole of Ferrara, Laboratory for Advanced Therapies (LTTA), Ferrara, Italy.
  • 5 Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, Ferrara, Italy.
  • 6 Department of Biosciences, Biotechnology and Environment, University of Bari "A. Moro", Bari, Italy.
PMID: 40399042 DOI: 10.1080/14756366.2025.2505907
Abstract

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.

Keywords

Permeability transition pore; cardiac ischaemia/reperfusion injury; cytoprotection; mPTP inhibitors; mitochondria.

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