Neurodegenerative diseases (NDs) constitute an escalating global health crisis characterised by irreversible neuronal deterioration, resulting in the progressive decline of cognitive abilities, motor functions, and ultimately, death. However, current therapeutic approaches remain largely focused on symptom management rather than disease modification. A common feature across various NDs is mitochondrial dysfunction, particularly impaired mitophagy – the selective degradation of damaged mitochondria through autophagy pathways. This quality control mechanism is crucial for maintaining cellular health, especially in post-mitotic neurons where dysfunction can lead to cellular death. Despite the clear link between impaired mitophagy and neurodegeneration, there are currently no clinically approved mitophagy activators, targeting the central nervous system (CNS). This significant therapeutic gap, combined with the rising prevalence of NDs in ageing populations, underscores the urgent need for developing CNS-active mitophagy modulators.
As part of our research program towards the development of small molecule mitophagy activators, we have sought to improve the CNS drug-like properties of the previously reported p62-mediated mitophagy inducer (PMI) scaffold. This optimisation was undertaken using a molecular hybridisation approach, which aimed to merge the PMI scaffold with a more drug-like oxadiazole scaffold that also displayed mitophagy-activating properties. Through this work, we have successfully developed robust synthetic routes to access our target library of hybrid structures and have gained valuable insights into the complexities involved in the development of CNS-active mitophagy activators.