Exploring Disulfide Bridge as a Tool to Improve Pioglitazone’s Neuroprotective Potential: Toward the Development of Prolonged‐Acting MAO‐B/PPARγ Modulators

Neurodegenerative diseases’ treatments still represent one of the major unmet medical needs, and their related clinical trials are characterized by one of the highest failure rates. Despite the promising preclinical premises, pioglitazone lies among those drugs that failed clinical translation. It is an antidiabetic drug acting as a PPARγ agonist and later repurposed as a competitive and selective MAO‐B inhibitor featuring polyhedral neuroprotective properties. In pursuing our efforts to broaden the therapeutic potential of pioglitazone toward the neurodegenerative context, we herein developed and preliminarily characterized a new series of glitazone derivatives. Particularly, by means of different connectors, a disulfide covalent warhead was attached to the 5‐benzylthiazolidine‐2,4‐dione head to potentially engage cysteines located in MAO‐B and PPARγ binding sites and turn pioglitazone into a prolonged‐acting modulator. Interestingly, compound 5 emerged as a selective competitive MAO‐B inhibitor and a PPARγ agonist with a very slow dissociation rate, revealing long‐lasting target engagement, albeit exhibiting lower potencies with respect to pioglitazone. This peculiar biological profile resulted in promising antioxidant and anti‐inflammatory properties, laying the ground for future development of covalent pioglitazone derivatives.