Dual antioxidant structures with potent anti-inflammatory, hypolipidemic and cytoprotective properties

Theodosis-Nobelos, Panagiotis; Athanasekou, Chrysoula; Rekka, Eleni A.

doi:10.1016/j.bmcl.2017.09.054

Cited by 17 publications

(9 citation statements)

References 32 publications

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“…Compounds 3 and 4 demonstrated significant efficacy, but not so great as Compounds 1 and 2 . All these four compounds were also found to possess antioxidant properties in our experiments, which may contribute to acute inflammation reduction, as we have previously reported [ 42 ]. Despite not exerting antioxidant potential, Compounds 5 and 6 could also inhibit rat paw oedema, since not only oxidative stress but various signaling pathways are involved in this process.…”

Section: Discussionsupporting

confidence: 84%

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

2022

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Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by memory loss and cognitive impairment. Its pathology has not been fully clarified and therefore highly effective treatments have not been obtained yet. Almost all the current treatment options aim to alleviate only the symptoms and not to eliminate the disease itself. Acetylcholinesterase inhibitors are the main therapeutic agents against AD, whereas oxidative stress and inflammation have been found to be of great significance for the development and progression of neurodegeneration. In this work, ethyl nipecotate (ethyl-piperidine-3-carboxylate), a heterocyclic carboxylic acid derivative, which acts as a GABA reuptake inhibitor and has been used in research for diseases involving GABAergic neurotransmission dysfunction, was amidated with various carboxylic acids bearing antioxidant and/or anti-inflammatory properties (e.g., ferulic acid, sinapic acid, butylated hydroxycinnamic acid). Most of our compounds have significant antioxidant potency as lipid peroxidation inhibitors (IC50 as low as 20 μΜ), as oxidative protein glycation inhibitors (inhibition up to 57%), and act as DPPH reducing agents. Moreover, our compounds are moderate LOX inhibitors (up to 33% at 100 μΜ) and could reduce rat paw edema induced by carrageenan by up to 61%. Finally, some of them possessed inhibitory activity against acetylcholinesterase (IC50 as low as to 47 μΜ). Our results indicate that our compounds could have the potentiality for further optimization as multi-targeting agents directed against AD.

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Section: Discussionsupporting

confidence: 84%

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

2022

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“…The antioxidant activity of 6 was almost seven times higher, compared with the 3,5-di-tert-butyl-4-hydroxybenzoic acid derivative 5 . This difference in the activity is confirmed by our previous results of compounds bearing these acids, and the equal inhibition in various concentrations of the compounds seems to be related to their physicochemical properties and not only to their antioxidant capacity [ 26 , 29 ].…”

Section: Discussionsupporting

confidence: 76%

“…We have previously reported that esters or amides of ibuprofen and ketoprofen enhanced the anti-inflammatory activity of the parent molecules [ 31 , 32 ], and that antioxidant acids such as Trolox amidated with L-cysteine or cysteamine yielded potent anti-inflammatory agents [ 29 ]. Unlike butylated hydroxytoluene which is devoid of anti-inflammatory activity [ 23 ], 3,5-di- tert -butyl-4-hydroxybenzoic acid derivatives possess significant anti-inflammatory activity, not always related to the antioxidant activity of the compounds, a finding that may partly be related to the lipoxygenase inhibitory activity of the compounds [ 23 , 26 , 29 , 31 , 33 ]. Additionally, since oxidative stress plays a critical role in inflammatory processes, compounds bearing the 3,5-di- tert -butyl-4-hydroxybenzyl moiety may offer considerable anti-inflammatory activity [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hypercholesterolemia and oxidized LDL cholesterol are the main contributors to the development of atherosclerosis and the progression of neurodegenerative disorders such as Alzheimer’s disease [ 27 , 45 ]. Furthermore, we have shown that amide derivatives of NSAIDs and antioxidants possess hypolipidemic properties [ 23 , 26 , 29 , 32 ]. Compounds with dual anti-inflammatory and antioxidant potential may improve the cardiovascular state of the patient via various mechanisms such as NF-κB reduction and Nrf2 amplification, together with the reduction in ox-LDL levels [ 46 ]…”

Section: Discussionmentioning

confidence: 99%

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Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

et al. 2021

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A series of L-serine amides of antioxidant acids, such as Trolox, (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (phenolic derivative of cinnamic acid) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (structurally similar to butylated hydroxytoluene), was synthesized. The hydroxy group of serine was esterified with two classical NSAIDs, ibuprofen and ketoprofen. The Trolox derivatives with ibuprofen (7) and ketoprofen (10) were the most potent inhibitors of lipid peroxidation (IC50 3.4 μΜ and 2.8 μΜ), several times more potent than the reference Trolox (IC50 25 μΜ). Most of the compounds decreased carrageenan-induced rat paw edema (37–67% at 150 μmol/kg). They were moderate inhibitors of soybean lipoxygenase, with the exception of ibuprofen derivative 8 (IC50 13 μΜ). The most active anti-inflammatory compounds exhibited a significant decrease in lipidemic indices in the plasma of Triton-induced hyperlipidemic rats, e.g., the most active compound 9 decreased triglycerides, total cholesterol and low-density lipoprotein cholesterol by 52%, 61% and 70%, respectively, at 150 μmol/kg (i.p.), similar to that of simvastatin, a well-known hypocholesterolemic drug. Since the designed compounds seem to exhibit multiple pharmacological actions, they may be of use for the development of agents against inflammatory and degenerative conditions.

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“…All these compounds exhibited free radical scavenging ability at concentrations of 5 µM, 10 µM, 50 µM, 100 µM, and 100 µM as compared with control material, respectively. Interestingly prepared compounds 6 – 8 showed higher DPPH radical scavenging activity than that of standard compound, trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) [ 32 ]. Additionally, compounds 6 – 8 showed good DPPH radical scavenging activity compared with trolox at the concentration of 50 and 100 µM.…”

Section: Resultsmentioning

confidence: 99%

Practical Synthesis of Chalcone Derivatives and Their Biological Activities

et al. 2017

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Practical synthesis and biological activities of 4-hydroxy-3-methoxy-2-propene derivatives are described. The novel chalcone derivatives were prepared by acid catalysed one-step condensation of 1,3- or 1,4-diacetylbenzene and 1,3,5-triacetylbenzene with 4-hydroxy-3-methoxybenzaldehyde. They were then evaluated for free radical scavenging activity, suppression of lipopolysaccharides (LPS)-induced NO generation, and anti-excitotoxicity in vitro. It was found that all compounds showed good effects for 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, LPS-induced NO generation, and anti-neurotoxicity. Compounds 6 and 7 were potent suppressor of NO generation with the concentration range 10 µM and especially compound 8 showed very potent anti-inflammatory activity with 1 µM. In addition, the di- and tri-acetylbenzyl derivatives 6, 7, and 8 showed enhanced anti-neurotoxicity activity in cultured cortical neurons. Molecular modelling studies to investigate the chemical structural characteristics required for the enhanced biological activities interestingly revealed that compound 8 has the smallest highest occupied molecular orbital-lowest energy unoccupied molecular orbital (HOMO-LUMO) gap, which signifies easy electron and radical transfer between HOMO and LUMO in model studies.

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Dual antioxidant structures with potent anti-inflammatory, hypolipidemic and cytoprotective properties

Cited by 17 publications

References 32 publications

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

Antioxidant Serine-(NSAID) Hybrids with Anti-Inflammatory and Hypolipidemic Potency

Practical Synthesis of Chalcone Derivatives and Their Biological Activities

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