Thiourea-Based H<sub>2</sub>S-Releasing Pramipexole Hybrids as Neuroprotective Agents.

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Multitarget hybrid molecules are a promising strategy for treating complex neurodegenerative disorders such as Parkinson's disease (PD), where dopaminergic dysfunction, oxidative stress, neuroinflammation, and cellular senescence coexist and drive disease progression. Here, we developed pramipexole-derived hydrogen sulfide (H2S)-releasing hybrids using, for the first time, a thiourea moiety as an H2S-donating linker to extend the therapeutic profile of pramipexole beyond dopamine receptor agonism. The hybrids were synthesized and characterized, and their H2S-releasing properties were assessed by amperometric and intracellular detection assays. Among the series, compound 2e (PRAM-ADA) showed the most efficient and sustained H2S release, indicating a favorable thiol-dependent release profile. PRAM-ADA was further evaluated for antioxidant and anti-senescent activities in BV2 microglial cells, as well as for chemical and enzymatic stability under simulated physiological conditions. The hybrid significantly reduced LPS-induced reactive oxygen species accumulation and attenuated oxidative stress-induced cellular senescence, demonstrating a superior cytoprotective profile compared with pramipexole. These findings support the concept that combining dopaminergic activity with controlled H2S donation enhances antioxidant and anti-senescent responses, indicating their potential as multitarget agents with neuroprotective properties relevant to neurodegenerative disorders, including PD.

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