Synthesis and evaluation of the anti-nociceptive and anti-inflammatory activity of 4-aminoquinoline derivatives

Santos, Raquel de Meneses; Barros, Pooline Rocha; Bortoluzzi, Janaína Heberle; Meneghetti, Mário R.; Silva, Yolanda Karla Cupertino da; Silva, Amanda Evelyn da; Santos, Mariana da Silva; Alexandre-Moreira, Magna Suzana

doi:10.1016/j.bmc.2015.06.029

Cited by 18 publications

(5 citation statements)

References 18 publications

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“…VR23 is especially notable because it is not only nontoxic and preferentially kills cancer over noncancer cells but also shows strong synergy when combined with other therapeutic agents, such as paclitaxel (16). In this article, we report that VR23 also possesses a strong antiinflammatory property, which is consistent with the notion that the 7-chloro-4-aminoquinoline group renders an anti-inflammatory property (37,42). The anti-inflammatory effect of VR23 is not specific to certain cell lines only because it can reduce the response in a number of different model systems, including monocyte cell lines, primary synoviocytes, and the bronchoalveolar system in mice.…”

Section: Discussionsupporting

confidence: 80%

“…Note that HCQ was included in this experiment as it is often used to treat RA and SLE (34)(35)(36). In addition, both HCQ and VR23 contain a 7-chloro-4-aminoquinoline group found in many anti-inflammatory molecules (37). Our findings thus indicate that VR23 can be effective and potentially safe for the treatment of RA patients.…”

Section: Vr23 Effectively Downregulates Il-6 In Human Synovial Cells mentioning

confidence: 83%

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The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

Durkin

Lee

2020

The Journal of Immunology

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We previously found that the novel VR23 proteasome inhibitor not only possesses an effective antitumor activity without causing any ill effects to animals but also reduces side effects caused by a partner drug when used in combination. In this article, we report that VR23, unlike other proteasome inhibitors, exhibits potent anti-inflammatory activity. In the LPS-induced THP-1 monocyte model, VR23 downregulates proinflammatory cytokines IL-1b, TNF-a, IL-6, and IL-8 at a similar efficacy to dexamethasone. In contrast, two well-known proteasome inhibitors, bortezomib and carfilzomib, do not effectively downregulate these proinflammatory cytokines. Data from a study with SW982 synovial cell line and primary human synoviocytes showed that VR23 not only effectively downregulates IL-6 but also inhibits cell migration. Interestingly, the IL-6 downregulation by VR23 was significantly more pronounced in the primary synovial cells from rheumatoid arthritis patients than those from healthy donors, suggesting that VR23 can be selective against rheumatoid arthritis. Finally, VR23 effectively reduces neutrophil migration, TNF-a secretion, and tissue inflammation in mice (female BALB/c strain) with an LPS-induced acute lung injury. Thus, our current data indicate that VR23 can be effective on both acute and chronic inflammatory conditions. Taken together with our previous work, VR23 is not only effective on inflammatory conditions but also applicable to different aspects of cancer control, including the treatment and prevention of tumor development by chronic inflammatory responses.

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Section: Discussionsupporting

confidence: 80%

Section: Vr23 Effectively Downregulates Il-6 In Human Synovial Cells mentioning

confidence: 83%

The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

Durkin

Lee

2020

The Journal of Immunology

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“…Aminoquinoline moiety is present in many biologically active compounds. Compounds bearing this sub-structure are described with anti-tuberculosis, 1 anti-leishmania 2 or antiinflammatory 3 , or antiviral (Ebola 4 ) activity or against Parkinson's disease 5 although an anti-malarial therapeutic indication is most well-known. The most used compounds of this family are chloroquine (CQ) and amodiaquine (AQ) ( Figure 1).…”

Section: -mentioning

confidence: 99%

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Gay

Renault

Coevoet

et al. 2018

Bioorganic & Medicinal Chemistry

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The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer's disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3 to 10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100µM.

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“…2,5 Quinoline moiety derivatives plays vital role in the development of numerous classes of newer drugs having various biological properties such as antimalarial, 6 anticancer, 7 antibacterial, 8 anti-tubercular, 9 and antiinflammatory and analgesic activities. [10][11][12][13] Moreover, glafenine, floctafenine and antrafenine (Figure 1) are analgesic and non-steroidal anti-inflammatory drugs (NSAIDs) related to the fenamate class and can be considered as 4-aminoquinolines. 14,15 Introducing another heterocyclic moiety to the quinolone ring initiates the activity, 12 as noticed by the piperazine heterocyclic pharmacophoric moiety.…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Analgesic Activities of 7-Chloro-4-(Piperazin-1-yl) Quinoline Derivative Mediated by Suppression of InflammatoryMediators Expression in Both RAW 264.7 and Mouse Models

et al. 2020

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Background: 4-Aminoquinoline derivatives possess various potential biological properties.The introduction of additional piperazine heterocyclic pharmacophoric moiety tends to haveprofound impact in increasing the activity. The present work was undertaken to investigate thein-vitro and in-vivo anti-inflammatory activity as well as the peripheral and central analgesicactivities of compound 1-(4-(7-chloroquinoline-4-yl)piperazin-1-yl)-2-(4-phenylpiperazin-1-yl)ethanone (5) in experimental models. Methods: The percentage inhibition of the lipopolysaccharide induced NO release of 7-chloro-4-(piperazin-1-yl)quinoline derivatives 1-9 was determined in RAW 264.7 murine macrophagemodel. Western blot analysis was performed to evaluate the effect of compound 5 on proteinexpression of inducible nitric oxide synthase (iNOS). Gene expression of inflammatory markerswas evaluated using real-time polymerase chain reaction. The peripheral and central analgesicactivities of compound 5 were evaluated in mice using writhing and hot-plate tests, respectively.Anti-inflammatory activity was assessed using carrageenan-induced paw edema assay in miceand serum NO and COX-2 levels were measured. Results: Compound 5 demonstrated the highest NO inhibitory activity that was accompaniedby inhibition of iNOS protein expression and decreased gene expression levels of inflammatorymarkers. It revealed a potential peripheral analgesic effect through inhibition of abdominalwrithing in mice treated with doses of 15 and 30 mg/kg and its effect was comparable to diclofenacsodium. Compound 5 possessed an analgesic activity starting from 15 min post administrationand reached its peak at 45 min which was significantly higher than that of tramadol hydrochloridesuggesting its potential as central analgesic agent. It also showed percentage of inhibition ofedema of 34, 50 and 64% at 1, 2, and 3 h respectively, post carrageenan challenge together with asignificant decrease in serum NO and COX-2 levels. Conclusion: The remarkable anti-inflammatory and analgesic activities of compound 5 couldbe attributed to the advantageous introduction of the heterocyclic 7-chloro-4-(piperazin1-yl)quinoline scaffold incorporated with N-phenylpiperzine functional groups linked together withthe ethanone pharmacophoric chain.

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Synthesis and evaluation of the anti-nociceptive and anti-inflammatory activity of 4-aminoquinoline derivatives

Cited by 18 publications

References 18 publications

The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

New phenylaniline derivatives as modulators of amyloid protein precursor metabolism

Anti-Inflammatory and Analgesic Activities of 7-Chloro-4-(Piperazin-1-yl) Quinoline Derivative Mediated by Suppression of InflammatoryMediators Expression in Both RAW 264.7 and Mouse Models

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