Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam

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

doi:10.3390/molecules24183277

Cited by 15 publications

(16 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its high lipophilicity allows it to approach DPPH effectively and interact with it, producing a stable phenolic radical due to the positive inductive effect of the tert -butyl substituents. Lipophilicity seems to be a significant property for interaction with DPPH since BHCA derivatives with high lipophilicity have shown to be effective DPPH reducing agents [ 28 , 31 ]. In contrast, Compound 1 produces a less stable phenolic radical after hydrogen abstraction and thus it could not reduce DPPH effectively even at 200 μΜ.…”

Section: Discussionmentioning

confidence: 99%

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

2022

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

2022

View full text Add to dashboard Cite

show abstract

“…Ibuprofen derivatives 8 and 9 were more active than ketoprofen derivatives 11 and 12 . This may partly be related to the less rigid structure of the former NSAID, since we have shown that rigid molecules seem to offer diminished activity [ 39 , 40 ]. 4-Hydroxy cinnamic acid shows low potency in LOX inhibition; however, compounds bearing this structure or the ( E )-phenyl-propene moiety show considerable activity on LOX inhibition [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…The final compounds were synthesized by esterification of the above acids with 3,4,5-trimethoxybenzyl alcohol, using DCC in the presence of 4-dimethylaminopyridine (DMAP) ( Scheme 3 and Figure 1 ) [ 17 ] with yields 43–80%. The spectroscopic (IR, 1 H-NMR, 13 C-NMR) studies and chemical analysis (C, H, N) were carried out to characterize the new compounds and support their molecular structures.…”

Section: Resultsmentioning

confidence: 99%

“…After 3.5 h, the hind paws were excised and weighed separately. The produced edema was estimated as paw weight increase [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

et al. 2022

Self Cite

View full text Add to dashboard Cite

The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs.

show abstract

Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam

Cited by 15 publications

References 22 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

Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol

Contact Info

Product

Resources

About