Design, Synthesis and Biological Evaluation of New Antioxidant and Neuroprotective Multitarget Directed Ligands Able to Block Calcium Channels

We report herein the design, synthesis and biological evaluation of new antioxidant and neuroprotective multitarget directed ligands (MTDLs) able to block Ca(2+) 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 Ca(2+) 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), Ca(2+) channel antagonist (46.95% at 10 μM), showing significant neuroprotection (38%) against H(2)O(2) at 10 μM, being considered thus a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.