Synthesis of Hantzsch Adducts as Cholinesterases and Calcium Flux inhibitors, Antioxidants and Neuroprotectives

Abstract

We report herein the design, synthesis, biological evaluation, and molecular modelling of new inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), able to block Ca+2 channels also showing antioxidant and neuroprotective activities. The new MTDL, dialkyl 2,6-dimethyl-4-(4-((5-aminoalkyl)oxy)phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 3a-p, have been obtained via Hantzsch reaction from appropriate and commercially available precursors. Pertinent biological analysis has prompted us to identify MTDL 3h [dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] as an attractive inhibitor of AChE (1.8 μM) and BuChE (2 μM), Ca+2 channel antagonist (47.72% at 10 μM), and antioxidant (2.54 TE) agent, showing significant neuroprotection 28.68% and 38.29% against H2O2, and O/R, respectively, at 0.3 μM, thus being considered a hit-compound for further investigation in our search for anti-Alzheimer’s disease agents.

Acetylcholinesterase Inhibitors in the Treatment of Neurodegenerative Diseases and the Role of Acetylcholinesterase in their Pathogenesis

“…In the second group, the compound best inhibiting AChE was the one containing chlorine in the C4 position, but it did not detect activity against BChE. In another study, dimethyl-4-(4-((5-(4-benzylpiperidin-1-yl)pentyl)oxy)phenyl)-2,6-dimethyl-1, 4-dihydropyridine-3,5-dicarboxylate was chosen as the compound most present in AD therapy [380]. It has shown multidirectional effects: anticholinesterase, antioxidant and neuroprotective, as well as inhibiting calcium flux.…”

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation

“…The evaluation of the calcium channel blockade of compounds BIGI 4a-d and BIGI 5a-d was carried out using FLIPR Calcium 6 indicator according to previously described protocols [35,36]. In brief, FLIPR-loaded SH-SY5Y cells were exposed to nimodipine (10 µM, reference inhibitor), DMSO (0.1%, vehicle), or our compounds of interest (10 µM) for 10 min.…”

Fused 1,4‐Dihydropyridines and Their Corresponding Pyridines: Synthesis, Molecular Modeling and Cholinesterase Inhibition

“…To clarify, Pachón et al. synthesized new dihydropyridine derivatives, among which compound ( a ) showed sufficient inhibitory power against acetylcholinesterase (IC 50 : 1.8 μM) and butyrylcholinesterase (IC 50 : 2.0 μM) [13] . In another study by Zafar et al., new 1,4‐dihydropyridine derivatives were synthesized (Figure 2).…”