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

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 2; p. 741
• Main Authors: Spasov, Alexander, Ovchinnikova, Irina, Fedorova, Olga, Titova, Yulia, Babkov, Denis, Kosolapov, Vadim, Borisov, Alexander, Sokolova, Elena, Klochkov, Vladlen, Skripka, Maria, Velikorodnaya, Yulia, Smirnov, Alexey, Rusinov, Gennady, Charushin, Valery
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.01.2023; MDPI
• Subjects: [1,2,4]triazolo[1,5-a]pyrimidines; Acute Lung Injury - chemically induced; Acute Lung Injury - drug therapy; Animal models; Animals; Anti-inflammatory agents; Biological activity; cytokine release; Cytokines; Cytotoxicity; Dexamethasone; Ethanol; Hydrocarbons; Immune system; Immunosuppressive agents; Inflammation; Innate immunity; Interleukin 6; Interleukin-6 - pharmacology; Kinases; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lung; lung injury; Lungs; Macrophages; Mice; Molecular weight; Nitric oxide; Pharmacophores; Protective Agents - pharmacology; Pyrimidines; Pyrimidines - chemistry; cytokine release; [1,2,4]triazolo[1,5-a]pyrimidines; pyrimidines; lung injury; inflammation
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28020741

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- ]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 , which was supported by biochemical, cytological and morphological markers.