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

Abstract

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.

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

“…Cinnamic acid and an array of its derivatives have been found to decrease carrageenan-induced inflammation, suppressing factors such as iNOS, COX-2 and NF-κB expression, as well as TNF-α [ 42 , 43 ]. Furthermore, we have shown that these 3-phenylacrylate moieties seem to enhance the anti-inflammatory potency in vivo and offer more than one pharmacological activity [ 32 , 33 , 35 ], whilst 3-(pyridin-3-yl)propan-1-ol insertion may offer movement towards this direction [ 30 , 44 ].…”

“…Lipid peroxidation was assessed spectrophotometrically (535/600 nm) as per the method using 2-thiobarbituric acid as the reagent. All compounds and solvents were found not to interfere with the assay [ 32 ].…”

“…Compounds (dissolved in absolute ethanol, final concentrations 50–200 μM) were added to an ethanolic solution of DPPH (final concentration 200 μM) at room temperature (22 ± 2 °C). Absorbance at 517 nm was recorded after 30 min against a blank sample [ 32 ].…”

“…(0.15 mmol/kg), 5 min before the carrageenan administration. The produced edema was measured after 3.5 h, as paw weight increase [ 32 ].…”

Synthesis, characterization and supramolecular analysis for (E)-3-(pyridin-4-yl)acrylic acid

“…Cinnamic acids are reactive molecules due to possessing an unsaturated carbonyl moiety, which can be considered a Michael acceptor and benzene ring. Both make it possible to modify them, resulting in synthetic cinnamic acid derivatives with a broad range of biological properties, including antibacterial (Ruwizhi & Aderibigbe, 2020) antituberculosis (Teixeira et al, 2020), antimalarial (Fonte et al, 2023), antidiabetic (Adisakwattana, 2017;Feng et al, 2022), anticancer (Feng et al, 2022, antifungal (Liu et al, 2024), Alzheimer's treatment (Drakontaeidi & Pontiki, 2024), antioxidant (Nouni et al, 2023), andcosmetic (Gunia-Krzyz ˙ak et al, 2018). Among the various types of cinnamic acids documented, 4-pyridylacrylic acid (4-Hpya) is considered a highly valuable ligand because of several structural characteristics that make it suitable for the construction of coordination compounds.…”