Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels
Irène Pachón-Angona, Solene Daniel, Hélène Martin, Alexandre Bonet, Artur Wnorowski, Maciej Maj, Krzysztof Jóźwiak, Tiago Silva, Bernard Refouvelet, Fernanda Borges, José Marco‐Contelles, Lhassane Ismaïli
Abstract
We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca2+ channels. New dialkyl 2,6-dimethyl-4-(4-(prop-2-yn-1-yloxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate MTDLs 3a–t, resulting from the juxtaposition of nimodipine, a Ca2+ channel antagonist, and rasagiline, a known MAO inhibitor, have been obtained from appropriate and commercially available precursors using a Hantzsch reaction. Pertinent biological analysis has prompted us to identify the MTDL 3,5-dimethyl-2,6–dimethyl–4-[4-(prop–2–yn–1-yloxy)phenyl]-1,4-dihydro- pyridine- 3,5-dicarboxylate (3a), as an attractive antioxidant (1.75 TE), Ca2+ channel antagonist (46.95% at 10 μM), showing significant neuroprotection (38%) against H2O2 at 10 μM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.