Pachón Angona, IreneBernard, Paul J.Simakov, AlexeyMaj, MaciejJozwiak, KrzysztofNovotna, AnnaLemke, CarinaGütschow, MichaelMartin, HeleneOset Gasque, María JesúsContelles, José MarcoIsmaili, Lhassane2024-12-022024-12-022024-01-17Pachón-Angona, I.; Bernard, P.J.; Simakov, A.; Maj, M.; Jozwiak, K.; Novotna, A.; Lemke, C.; Gütschow, M.; Martin, H.; Oset-Gasque, M.-J.; et al. Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties. Pharmaceutics 2024, 16, 121. https://doi.org/10.3390/pharmaceutics 160101211999-492310.3390/pharmaceutics16010121https://hdl.handle.net/20.500.14352/1119032023 Descuento MDPIThis work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.3390/pharmaceutics16010121open accessCalcium channel inhibitorsProteases inhibitorsAntioxidant response elementORACAlzheimer’s diseaseFarmacia24 Ciencias de la Vida