Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives and Analogs Targeting the NLRP3 Inflammasome

Pan, Liangkun; Nan, Hang; Zhang, Chao; Chen, Yu; Li, Shuchun; Sun, Yang; Li, Zhongjun; Meng, Xiangbao

doi:10.3390/molecules22020213

Cited by 20 publications

(9 citation statements)

References 32 publications

(42 reference statements)

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“…A broader series was synthesized consisting of analogues retaining an EWG in this position, as well as alternatives to the benzimidazole scaffold. 310 The most potent compound of this series, AI-33 ( Fig. 4D ), has an IC 50 of only around 10 μM; however, this series does represent a potential new approach to inhibiting NLRP3-dependent IL-1β release.…”

Section: Contribution Of Inflammasomes To Cns Diseasementioning

confidence: 97%

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Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

et al. 2018

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Neuroinflammation is becoming increasingly recognized as a critical factor in the pathology of both acute and chronic neurological conditions. Inflammasomes such as the one formed by NACHT, LRR, and PYD domains containing protein 3 (NLRP3) are key regulators of inflammation due to their ability to induce the processing and secretion of interleukin 1β (IL-1β). IL-1β has previously been identified as a potential therapeutic target in a variety of conditions due to its ability to promote neuronal damage under conditions of injury. Thus, inflammasome inhibition has the potential to curtail inflammatory signaling, which could prove beneficial in certain diseases. In this review, we discuss the evidence for inflammasome contributions to the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, epilepsy, and acute degeneration following brain trauma or stroke. In addition, we review the current landscape of drug development targeting the NLRP3 inflammasome.

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Section: Contribution Of Inflammasomes To Cns Diseasementioning

confidence: 97%

“…308 Structurally similar thiabendazole analogues 309 can also act as anti-inflammatory agents. 310 An early lead, TBZ-09, inhibits the release of IL-1β and exhibits the structural feature of an electron withdrawing group (EWG) at position 5 of the benzimidazole core ( Fig. 4D ).…”

Section: Contribution Of Inflammasomes To Cns Diseasementioning

confidence: 99%

Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

et al. 2018

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“…It is well established that NLRP3 is a critical component of NLRP3 inflammasome and being involved in inflammatory diseases. 5,19,20 We first determined the expression of NLRP3 and the therapeutic potential of nodakenin. As shown in Figure 3A, the results showed that an obvious rise of protein level of NLRP3 expression by immunohistochemistry is primarily located in renal tubules after ischaemiareperfusion injury.…”

Section: Nodakenin-inhibited Nlrp3 Inflammasome Activation In Vivomentioning

confidence: 99%

Nodakenin alleviates renal ischaemia‐reperfusion injury via inhibiting reactive oxygen species‐induced NLRP3 inflammasome activation

Yuan

Lin

et al. 2020

Nephrology

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Background: Acute kidney injury (AKI) is a vital contributor to chronic kidney disease and limited therapeutic options are existed to preserve the renal injury. The research presented here investigated the protective effect of nodakenin against AKI and the underlying mechanism. Methods: The effect of nodakenin was investigated in ischaemia reperfusion-induced renal injury (IRI) of AKI mice and hypoxia-treated primary renal tubular cells. Briefly, renal functions including creatinine and urea nitrogen were determined and mechanisms associated inflammation were investigated by the advantage of immunohistochemistry, western blot, RT-PCR and flow cytometry. Results: Deterioration of renal functions including and creatinine, urea nitrogen and tubular necrosis were observed in IRI-AKI model. In contrast, nodakenin strikingly alleviated the deterioration of creatinine, urea nitrogen and tubular necrosis when compared with IRI model. Moreover, nodakenin could significantly inhibit the expression of pro-inflammatory cytokines including interleukin (IL)-1β, IL-6 and tumour necrosis factor-α both in hypoxia-treated primary renal tubular cells and in AKI model. Mechanistic studies revealed that nodakenin dramatically suppressed the production of reactive oxygen species and subsequent NLPR3 inflammasome activation. Conclusion: In summary, these findings provided a solid evidence base and a new drug option for the treatment of AKI.

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“… 18 Moreover, Pan et al synthesized novel benzimidazole derivatives and identified, in vitro, out of 34 compounds, several with an anti-inflammatory effect. 19 Faour et al also evaluated four series of newly synthesized bipyrazoles for their anti-inflammatory and analgesic activities. Two compounds showed superior anti-inflammatory activity compared to diclofenac and similar analgesic activity with minimal ulcerogenic side effect.…”

Section: Introductionmentioning

confidence: 99%

Investigation of chronic efficacy and safety profile of two potential anti-inflammatory bipyrazole-based compounds in experimental animals

Domiati

Mehanna

Ragab

et al. 2018

JIR

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PurposeAlthough nonsteroidal anti-inflammatory drugs are widely used to treat a variety of disorders, their administration is associated with gastrointestinal side effects, acute kidney injury and liver enzymes’ elevation. Accordingly, researchers are encouraged to create novel agents with better safety profile. The aim of the current study was to evaluate the chronic efficacy and safety profile of two compounds previously proven to have acceptable acute anti-inflammatory and analgesic activities.Materials and methodsDoses were determined through formalin-induced mice paw edema-based dose–response curves. Granuloma weight was used to assess the chronic effect of the investigated compounds as compared to the vehicle and diclofenac representing the positive and the negative controls, respectively. Mice kidneys, livers and stomachs were histologically examined. Moreover, troponin I, alanine aminotransferase, aspartate aminotransferase, serum creatinine and blood urea nitrogen levels were measured.ResultsThe results highlight that the granulomas and exudates developed in mice after 7 days of treatment, with compound I and compound II were significantly lower than that of the negative control group. Moreover, compound I showed significantly better anti-inflammatory effect than diclofenac. Troponin level was undetected in all groups. Histopathological examination of the stomach revealed normal mucosa for both tested compounds and controls. Likewise, kidneys showed neither significant histologic alteration nor biomarkers increase as compared to the control over both 7- and 30-day treatment periods. Mice that received the tested compounds or diclofenac exhibited transient liver damage specifically; congestion, vacuolization, necrosis and inflammation after 7 days of treatment which decreased significantly after 30 days of treatment as emphasized by the Suzuki score and biomarker levels.ConclusionSince the tested compounds, specifically compound I, presented a satisfactory chronic safety profile as well as anti-inflammatory effect, it is worth conducting further molecular pharmacological, toxicological and bioavailability studies to elucidate the efficacy of these potential anti-inflammatory bipyrazole compounds.

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Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives and Analogs Targeting the NLRP3 Inflammasome

Cited by 20 publications

References 32 publications

Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery?

Nodakenin alleviates renal ischaemia‐reperfusion injury via inhibiting reactive oxygen species‐induced NLRP3 inflammasome activation

Investigation of chronic efficacy and safety profile of two potential anti-inflammatory bipyrazole-based compounds in experimental animals

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