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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative pathology characterized by a highly interconnected biological processes leading to neuronal death, accumulation and aggregation of abnormal extracellular deposits of beta-amyloid peptide (Aβ) and neurofibrillary tangles, composed of hyperphosphorylated tau protein [1], and low level of neurotransmitter acetylcholine
1 H- and 13 C-NMR spectra were recorded on a Bruker (Wissembourg France) spectrometer, operating at 400 and 100 MHz, respectively, in solution in dimethylsulfoxide (DMSO-d6 )
The most active compounds were those with n = 1 linker length, with R1 = H (3a) and R1 = Cl (3h)
Summary
Alzheimer’s disease (AD) is a neurodegenerative pathology characterized by a highly interconnected biological processes leading to neuronal death, accumulation and aggregation of abnormal extracellular deposits of beta-amyloid peptide (Aβ) and neurofibrillary tangles, composed of hyperphosphorylated tau protein [1], and low level of neurotransmitter acetylcholine. New strategies, based on the multitarget directed ligand (MTDL) approach [2,3], have been developed for the design of new drugs able to bind simultaneously at diverse enzymatic systems or receptors involved in the progress of AD [4,5,6,7,8]. Following this paradigm a number of MTDLs has been described by many research groups [9,10,11].
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