Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury

Spasov, A. A.; Косолапов, В. А.; Babkov, Denis A.; Klochkov, Vladlen; Sokolova, Elena; Мирошников, М. В.; Борисов, А. В.; Velikorodnaya, Yulia; Смирнов, А. В.; Саватеев, Константин В.; Fedotov, Victor V.; Kotovskaya, S. K.; Русинов, В. Л.

doi:10.3390/ph15050537

Cited by 8 publications

(3 citation statements)

References 48 publications

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“…There is an evident demand for development of novel effective and safe drugs against severe complications of infectious diseases, including COVID-19 and bacterial pneumonias. Previously, we described nitro-azolo[1,5- a ]pyrimidines and quinazoline-2,4(1 H ,3 H )-diones with anti-inflammatory and protective activity against LPS-induced acute lung injury [ 32 , 33 ]. The synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5- a ]-pyrimidines was carried out.…”

Section: Discussionmentioning

confidence: 99%

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury

et al. 2023

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The problem of lung damage originating from excessive inflammation and cytokine release during various types of infections remains relevant and stimulates the search for highly effective and safe drugs. The biological activity of the latter may be associated with the regulation of hyperactivation of certain immune cells and enzymes. Here, we propose the design and synthesis of amino derivatives of 4,6- and 5,7-diaryl substituted pyrimidines and [1,2,4]triazolo[1,5-a]pyrimidines as promising double-acting pharmacophores inhibiting IL-6 and NO. The anti-inflammatory activity of 14 target compounds was studied on isolated primary murine macrophages after LPS stimulation. Seven compounds were identified to inhibit the synthesis of nitric oxide and interleukin 6 at a concentration of 100 µM. The most active compounds are micromolar inhibitors of IL-6 secretion and NO synthesis, showing a minimal impact on innate immunity, unlike the reference drug dexamethasone, along with acceptable cytotoxicity. Evaluation in an animal model of acute lung injury proved the protective activity of compound 6e, which was supported by biochemical, cytological and morphological markers.

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Section: Discussionmentioning

confidence: 99%

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury

et al. 2023

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“…In our study, hematoxylin/eosin and Masson staining protocols revealed clear pathological injuries in the mouse model of ALI caused by LPS administration, such as alveolar septum enlargement, hemorrhage, effusion, congestion, as well as increased pulmonary brosis. Excessive cytokine-mediated in ammation plays a crucial role in the development of ALI, and there is substantial evidence that sustained elevation of proin ammatory cytokines, such as TNF-α and IL-6, in bronchoalveolar lavage uid is associated with poor prognosis in patients with acute respiratory distress syndrome 22,23 . In this study, we found that intraperitoneal administration of LPS signi cantly increased TNF-α, IL-1β, and IL-6 concentrations in the lung tissue.…”

Section: Discussionmentioning

confidence: 99%

METTL3-m6A methylation inhibits Type II Alveolar Epithelial Cells proliferation and viability by promoting PTEN mRNA stability and translation efficiency in the acute lung injury

Zhuang

Wang

Shen

et al. 2022

Preprint

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Acute lung injury (ALI) is a life-threatening acute inflammatory disease with high morbidity and mortality rates. N6-methylation of adenosine (m6A) is an abundant mRNA nucleotide modification, which is critical for mRNA metabolism and function. However, the role of m6A modifications in ALI progression remains unclear. To address this problem, we modeled ALI in vivo by intraperitoneally injecting lipopolysaccharide (LPS) to C57BL/6 mice. In addition, we isolated alveolar type II cells (AECII) from the lungs of C57BL/6 mice and treated them in vitro with various concentrations of LPS. An m6A RNA methylation quantification kit was used to detect methylation levels. An m6A microarray and mRNA transcriptomic sequencing were used to screen the downstream targets of methyltransferase-like 3 (METTL3)-mediated m6A modifications. Gene and protein expression levels were determined by qRT-PCR and western blotting. The biological effects of modulating METTL3 expression level were evaluated both in vitro and in vivo. The binding between proteins and mRNA was verified by the RNA immunoprecipitation assay. The CCK-8 and EdU assays were used to examine changes in AECII viability and proliferation. The global number of mRNA m6A-modified loci and the “writer” methyltransferase METTL3 expression were significantly increased in the lung tissue following ALI and in LPS-treated AECII. METTL3 knockdown reduced the viability and proliferation of LPS-treated AECII. Furthermore, METTL3-mediated m6A modification of phosphatase and tensin homolog (Pten) mRNA enhanced its stability. Collectively, our results showed that METTL3 contributes to ALI progression by increasing stability and translation efficiency of Pten mRNA by means of m6A modification, indicating that METTL3 might become a new and innovative therapeutic target for the treatment of ALI.

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“…Primary peritoneal murine macrophages were isolated as we described previously 27 and LDH assay was performed as per standard procedure.…”

Section: Methodsmentioning

confidence: 99%

3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents

Babkov

Bezsonova

Сиротенко

et al. 2023

Bioorganic & Medicinal Chemistry Letters

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Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury

Cited by 8 publications

References 48 publications

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury

Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury

METTL3-m6A methylation inhibits Type II Alveolar Epithelial Cells proliferation and viability by promoting PTEN mRNA stability and translation efficiency in the acute lung injury

3-Arylidene-2-oxindoles as GSK3β inhibitors and anti-thrombotic agents

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