{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:17:19Z","timestamp":1779297439017,"version":"3.51.4"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Multitarget hybrid molecules are a promising strategy for treating complex neurodegenerative disorders such as Parkinson\u2019s 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\u2013induced 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.<\/jats:p>","DOI":"10.3390\/antiox15050628","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:39:34Z","timestamp":1779295174000},"page":"628","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thiourea-Based H2S-Releasing Pramipexole Hybrids as Neuroprotective Agents"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0617-156X","authenticated-orcid":false,"given":"Angela","family":"Corvino","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Citi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56125 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4282-2788","authenticated-orcid":false,"given":"Antonia","family":"Scognamiglio","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2090-7107","authenticated-orcid":false,"given":"Alma","family":"Martelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56125 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56125 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8836-8713","authenticated-orcid":false,"given":"Giulia","family":"Neggiani","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum\u2014Universit\u00e0 di Bologna, Corso d\u2019Augusto 237, 47921 Rimini, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2461-8214","authenticated-orcid":false,"given":"Carmela","family":"Fimognari","sequence":"additional","affiliation":[{"name":"Department for Life Quality Studies, Alma Mater Studiorum\u2014Universit\u00e0 di Bologna, Corso d\u2019Augusto 237, 47921 Rimini, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7357-5751","authenticated-orcid":false,"given":"Ferdinando","family":"Fiorino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9930-9467","authenticated-orcid":false,"given":"Elisa","family":"Magli","sequence":"additional","affiliation":[{"name":"Department of Public Health, School of Medicine, University of Naples Federico II, Via Panzini, 5, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4221-5560","authenticated-orcid":false,"given":"Rosa","family":"Sparaco","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Santagada","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Caliendo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3887-8869","authenticated-orcid":false,"given":"Beatrice","family":"Severino","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Medicine, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17013","DOI":"10.1038\/nrdp.2017.13","article-title":"Parkinson disease","volume":"3","author":"Poewe","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S0140-6736(23)01478-2","article-title":"The pathogenesis of Parkinson\u2019s disease","volume":"403","author":"Morris","year":"2024","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1212\/WNL.0b013e3181a1d44c","article-title":"The scientific and clinical basis for the treatment of Parkinson disease","volume":"72","author":"Olanow","year":"2009","journal-title":"Neurology"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Chakrabarti, S., and Bisaglia, M. (2023). Oxidative Stress and Neuroinflammation in Parkinson\u2019s Disease: The Role of Dopamine Oxidation Products. Antioxidants, 12.","DOI":"10.3390\/antiox12040955"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41392-023-01353-3","article-title":"Signaling pathways in Parkinson\u2019s disease: Molecular mechanisms and therapeutic interventions","volume":"8","author":"Yong","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1385\/MN:26:1:013","article-title":"Hydrogen sulfide as a neuromodulator","volume":"26","author":"Kimura","year":"2002","journal-title":"Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9049782","DOI":"10.1155\/2016\/9049782","article-title":"Physiological Importance of Hydrogen Sulfide: Emerging Potent Neuroprotector and Neuromodulator","volume":"2016","author":"Panthi","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Dogaru, B.G., and Munteanu, C. (2023). The Role of Hydrogen Sulfide (H2S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612555"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/j.1474-9726.2009.00543.x","article-title":"Neuroprotective effects of hydrogen sulfide on Parkinson\u2019s disease rat models","volume":"9","author":"Hu","year":"2010","journal-title":"Aging Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1038\/ncomms2623","article-title":"Sulfhydration mediates neuroprotective actions of parkin","volume":"4","author":"Vandiver","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sita, G., Hrelia, P., Tarozzi, A., and Morroni, F. (2016). Isothiocyanates Are Promising Compounds against Oxidative Stress, Neuroinflammation and Cell Death that May Benefit Neurodegeneration in Parkinson\u2019s Disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17091454"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1177\/09731296231187443","article-title":"Investigation of Neuroprotective Effects of Sulforaphane and Allyl Isothiocyanate in an in vitro Alzheimer\u2019s Disease Model","volume":"19","author":"Hacet","year":"2023","journal-title":"Pharmacogn. Mag."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Olayanju, J.B., Bozic, D., Naidoo, U., and Sadik, O.A. (2024). A Comparative Review of Key Isothiocyanates and Their Health Benefits. Nutrients, 16.","DOI":"10.3390\/nu16060757"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s11033-018-4465-4","article-title":"Allyl isothiocyanate attenuates oxidative stress and inflammation by modulating Nrf2\/HO-1 and NF-\u03baB pathways in traumatic brain injury in mice","volume":"46","author":"Caglayan","year":"2019","journal-title":"Mol. Biol. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5977","DOI":"10.1021\/acs.orglett.9b02117","article-title":"Isothiocyanates as H2S Donors Triggered by Cysteine: Reaction Mechanism and Structure and Activity Relationship","volume":"21","author":"Lin","year":"2019","journal-title":"Org. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"116636","DOI":"10.1016\/j.ejmech.2024.116636","article-title":"Isothiocyanate-Corticosteroid Conjugates against asthma: Unity makes strength","volume":"275","author":"Scognamiglio","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4612","DOI":"10.1038\/s41598-019-40925-8","article-title":"Memantine prodrug as a new agent for Alzheimer\u2019s Disease","volume":"9","author":"Sestito","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117175","DOI":"10.1016\/j.ejmech.2024.117175","article-title":"Design, synthesis and biological evaluation of new H2S-releasing rivastigmine derivatives as neuroprotective molecules","volume":"283","author":"Sestito","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0922-4106(95)90013-6","article-title":"Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors","volume":"290","author":"Mierau","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102941","DOI":"10.1016\/j.bioorg.2019.102941","article-title":"Evaluation of thioamides, thiolactams and thioureas as hydrogen sulfide (H2S) donors for lowering blood pressure","volume":"88","author":"Zaorska","year":"2019","journal-title":"Bioorg. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105039","DOI":"10.1016\/j.phrs.2020.105039","article-title":"Searching for novel hydrogen sulfide donors: The vascular effects of two thiourea derivatives","volume":"159","author":"Citi","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1212\/WNL.50.5.1323","article-title":"Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson\u2019s disease","volume":"50","author":"Fang","year":"1998","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17977","DOI":"10.1073\/pnas.0705710104","article-title":"Hydrogen sulfide mediates the vasoactivity of garlic","volume":"104","author":"Benavides","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-59745-361-5_3","article-title":"Methods to detect biomarkers of cellular senescence: The senescence-associated beta-galactosidase assay","volume":"371","author":"Itahana","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"401264","DOI":"10.1155\/2012\/401264","article-title":"Oxidative stress and microglial cells in Parkinson\u2019s disease","volume":"2012","author":"Peterson","year":"2012","journal-title":"Mediat. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.cnr.2006.09.006","article-title":"Neuroinflammation, Oxidative Stress and the Pathogenesis of Parkinson\u2019s Disease","volume":"6","author":"Mosley","year":"2006","journal-title":"Clin. Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhou, L., and Wang, Q. (2023). Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function. Antioxidants, 12.","DOI":"10.3390\/antiox12030652"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2792348","DOI":"10.1155\/2022\/2792348","article-title":"Hydrogen Sulfide Attenuates the Cognitive Dysfunction in Parkinson\u2019s Disease Rats via Promoting Hippocampal Microglia M2 Polarization by Enhancement of Hippocampal Warburg Effect","volume":"2022","author":"Tian","year":"2022","journal-title":"Oxid. Med. Cell. Longev."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/628\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T16:56:32Z","timestamp":1779296192000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/5\/628"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":28,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["antiox15050628"],"URL":"https:\/\/doi.org\/10.3390\/antiox15050628","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}