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

Theodosis-Nobelos, Panagiotis; Papagiouvannis, Georgios; Tziona, Paraskevi; Kourounakis, Panos N.; Rekka, Eleni A.

doi:10.3390/molecules26134060

Cited by 12 publications

(11 citation statements)

References 46 publications

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“…The parent NSAIDs and antioxidants BHB, BHBA and Trolox have little or no inhibitory activity, except for Naproxen ( c ), and its reduced analog (alcohol) d , which exhibits IC 50 values of 25 and 29 μM, respectively. The little or no inhibition (IC 50 > 200 μM) of LOX-3 by most other parent NSAID molecules ( a – n ), as also observed in the literature [ 17 , 18 , 19 ], supports the fact that the incorporation of the two pharmacophores in one structure leads to an improved interaction with the enzyme.…”

Section: Resultssupporting

confidence: 76%

Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

2021

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Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1–17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.

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Section: Resultssupporting

confidence: 76%

Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

2021

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“…The reaction was monitored for 7 min at 28 °C, recording the absorbance at 234 nm. Nordihydroguaiaretic acid (NDGA) was used as a reference [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

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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“…Similarly, compounds 4 and 5 also considerably lowered lipid levels, although they presented weak or no activity in all other experiments. It could be suggested that the (methoxy)cinnamyl moiety is responsible for this effect, since it has been reported that many cinnamic acid derivatives possessed hypolipidemic activity [ 53 , 54 ]. Of course, other factors may be related to this lipid decrease in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Nordihydroguaiaretic acid was used as a reference. For the estimation of the type of inhibition, the described experiments were repeated, using sodium linoleate at a concentration (1 mM) higher than the saturating substrate concentration [ 53 ].…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis and Evaluation of Antioxidant and NSAID Derivatives with Antioxidant, Anti-Inflammatory and Plasma Lipid Lowering Effects

Theodosis-Nobelos,

Marc,

Rekka

2024

Molecules

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Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such moieties was based on the design of structures with two or more molecular characteristics. The novel compounds were tested for their antioxidant, anti-inflammatory and hypolipidemic properties. Several compounds were potent antioxidants, comparable to the well-known antioxidant, Trolox. In addition, the radical scavenging activity of compound 6 reached levels that were slightly better than that of Trolox. All the tested compounds demonstrated remarkable activity in the reduction in carrageenan-induced rat paw edema, up to 59% (compound 2, a dual antioxidant and anti-inflammatory molecule, with almost 2.5-times higher activity in this experiment than the parent NSAID). Additionally, the compounds caused a significant decrease in the plasma lipidemic indices in Triton-induced hyperlipidemic rats. Compound 2 decreased total cholesterol by 75.1% and compound 3 decreased triglycerides by 79.3% at 150 μmol/kg (i.p.). The hypocholesterolemic effect of the compounds was comparable to that of simvastatin, a well-known hypocholesterolemic drug. Additionally, all compounds lowered blood triglycerides. The synthesized compounds with multiple activities, as designed, may be useful as potential candidates for conditions involving inflammation, lipidemic deregulation and oxygen toxicity.

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

Cited by 12 publications

References 46 publications

Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

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

Design, Synthesis and Evaluation of Antioxidant and NSAID Derivatives with Antioxidant, Anti-Inflammatory and Plasma Lipid Lowering Effects

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