Fernando Cagide-Fagín
PC6 – Fernando Cagide-Fagín
RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Porto, Portugal
ORCID
fernando.fagin@med.up.pt
| Hydroxypyridin-4-one-based ligands as multifunctional therapeutics for neurodegenerative diseases |
| Fernando Cagide1, Carla Lima2, Sofia Benfeito1, Daniel Chavarria1, Lisa Sequeira1, Bárbara Albuquerque1, Paula Serrão1, Patrício Soares-da-Silva1, Fernanda Borges1,2 1 RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal 2 RISE-Health, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal |
| Abstract Neurodegenerative disorders are complex, multifactorial diseases driven by interconnected pathological processes, including neurotransmitter imbalance, oxidative stress, mitochondrial dysfunction, and metal dyshomeostasis. In Parkinson’s disease (PD), dopamine depletion and iron accumulation are two closely linked hallmarks that contribute to disease progression. Catechol-O-methyltransferase (COMT) plays a central role in dopamine degradation, and its inhibition is a validated therapeutic strategy for PD. However, current COMT inhibitors such as tolcapone, entacapone, and opicapone are limited by hepatotoxicity and poor brain penetration. Their activity depends on a nitrocatechol motif that coordinates the enzyme’s magnesium cofactor, but the nitro group is also associated with toxicity, underscoring the need for safer alternatives. Here, we explore multitarget-directed ligands (MTDLs) as a strategy to address these converging pathological mechanisms. MTDLs are designed to combine multiple pharmacophores within a single chemical entity to simultaneously modulate dopamine dysregulation and iron-induced oxidative stress. Building on our previously identified brain-penetrant and selective COMT inhibitor (compound 9), we designed and synthesized a small library of hydroxypyridin-4-one-based derivatives incorporating iron-chelating motifs. The compounds were evaluated for COMT inhibition, metal-binding selectivity, and cytotoxicity. Several derivatives showed selective COMT inhibition, preferential binding of Cu(II) over Fe(II) and Mg(II), and no cytotoxicity at 25 µM. The results obtained so far will be presented in this communication. |
| References [1] Spahr, L.; Rubbia-Brandt, L.; Burkhard, P.R.; Assal, F.; Hadengue, A. Dig. Dis. Sci. 2000, 45 (9):1881-1884. [2] GParashos, S.A., Wielinski, C.L.; Kern, J.A. Clin. Neuropharmacol. 2004, 27 (3), 119-123. [3] Robinson, R.G.; Smith, S.M.; et al. ACS Chem. Neurosci. 2012, 3 (2), 129-140. Acknowledgments: This work was funded by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the FCT-Foundation for Science and Technology under research grants for RISE-Health (UID/06397/2025,) and RESTORE (COMPETE2030-FEDER-00776500 and 2023.17955.ICDT). This work was also funded by project IMPULSE and services of EU-OPENSCREEN (Horizon Europe: 101132028; DOI: 10.3030/101132028). C.L. (UI/BD/154557/2023) and B.A (2025.00893.BD) grant and D.C. (2024.07926.CEECIND) and S.B. (2023.06106.CEECIND/CP2833/CT0003) contracts were also supported by FCT and FEDER/COMPETE funds. |