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

Angona, Irene Pachón; Daniel, Solene; Martin, Hélène; Bonet, Alexandre; Wnorowski, Artur; Maj, Maciej; Jóźwiak, Krzysztof; Silva, Tiago; Refouvelet, Bernard; Borges, Fernanda; Marco‐Contelles, José; Ismaïli, Lhassane

doi:10.3390/molecules25061329

Cited by 12 publications

(4 citation statements)

References 41 publications

(77 reference statements)

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“…The calcium channel blockade assay was performed as described earlier [ 29 ]. Briefly, the SH-SY5Y cells were seeded out in 96-well dark-walled plates at a density of 1 × 10 5 cells per well.…”

Section: Methodsmentioning

confidence: 99%

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

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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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.

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Section: Methodsmentioning

confidence: 99%

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

Angona¹,

Martin²,

Daniel³

et al. 2020

IJMS

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show abstract

“…Variations in their functioning disrupt the plateau phase of cardiac operations and may trigger irregular conduction cycles, resulting in cardiac dysfunction [ 17 , 18 ]. The primary purpose of the calcium channel is to carry calcium ions into cells [ 19 , 20 ]. The influx of calcium ions from the extracellular space to cells increases the positive potential of cell membranes, and the calcium ions released from the sarcoplasmic reticulum indicate the contraction of cardiac myocytes [ 21 ].…”

Section: Calcium Channelsmentioning

confidence: 99%

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency

et al. 2023

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Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure–activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail.

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“…Assessment of calcium channel blockade of compounds 4a-i was performed according to the previously described protocol using the FLIPR calcium indicator 6 [59]. Briefly, FLIPR-loaded SH-SY5Y cells were exposed for 10 min to a 10 µm concentration of the tested compounds and to nimodipine used as a reference.…”

Section: Calcium Channel Inhibitionmentioning

confidence: 99%

Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer’s Disease Treatment

Dakhlaoui

Bernard

Pietrzak

et al. 2023

IJMS

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.

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

Cited by 12 publications

References 41 publications

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

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

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency

Exploring the Potential of Sulfonamide-Dihydropyridine Hybrids as Multitargeted Ligands for Alzheimer’s Disease Treatment

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