Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury
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...
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/2/741 |
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| author | Alexander Spasov Irina Ovchinnikova Olga Fedorova Yulia Titova Denis Babkov Vadim Kosolapov Alexander Borisov Elena Sokolova Vladlen Klochkov Maria Skripka Yulia Velikorodnaya Alexey Smirnov Gennady Rusinov Valery Charushin |
| author_facet | Alexander Spasov Irina Ovchinnikova Olga Fedorova Yulia Titova Denis Babkov Vadim Kosolapov Alexander Borisov Elena Sokolova Vladlen Klochkov Maria Skripka Yulia Velikorodnaya Alexey Smirnov Gennady Rusinov Valery Charushin |
| author_sort | Alexander Spasov |
| collection | DOAJ |
| description | 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-<i>a</i>]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 <b>6e</b>, which was supported by biochemical, cytological and morphological markers. |
| first_indexed | 2024-03-09T11:35:02Z |
| format | Article |
| id | doaj.art-7e0ceab1ee0941dc94010563981558dd |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T11:35:02Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-7e0ceab1ee0941dc94010563981558dd2023-11-30T23:44:13ZengMDPI AGMolecules1420-30492023-01-0128274110.3390/molecules28020741Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung InjuryAlexander Spasov0Irina Ovchinnikova1Olga Fedorova2Yulia Titova3Denis Babkov4Vadim Kosolapov5Alexander Borisov6Elena Sokolova7Vladlen Klochkov8Maria Skripka9Yulia Velikorodnaya10Alexey Smirnov11Gennady Rusinov12Valery Charushin13Department of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620108, RussiaI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620108, RussiaI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620108, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaDepartment of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, RussiaI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620108, RussiaI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Yekaterinburg 620108, RussiaThe 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-<i>a</i>]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 <b>6e</b>, which was supported by biochemical, cytological and morphological markers.https://www.mdpi.com/1420-3049/28/2/741pyrimidines[1,2,4]triazolo[1,5-<i>a</i>]pyrimidinesinflammationlung injurycytokine release |
| spellingShingle | Alexander Spasov Irina Ovchinnikova Olga Fedorova Yulia Titova Denis Babkov Vadim Kosolapov Alexander Borisov Elena Sokolova Vladlen Klochkov Maria Skripka Yulia Velikorodnaya Alexey Smirnov Gennady Rusinov Valery Charushin Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury Molecules pyrimidines [1,2,4]triazolo[1,5-<i>a</i>]pyrimidines inflammation lung injury cytokine release |
| title | Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury |
| title_full | Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury |
| title_fullStr | Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury |
| title_full_unstemmed | Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury |
| title_short | Amino Derivatives of Diaryl Pyrimidines and Azolopyrimidines as Protective Agents against LPS-Induced Acute Lung Injury |
| title_sort | amino derivatives of diaryl pyrimidines and azolopyrimidines as protective agents against lps induced acute lung injury |
| topic | pyrimidines [1,2,4]triazolo[1,5-<i>a</i>]pyrimidines inflammation lung injury cytokine release |
| url | https://www.mdpi.com/1420-3049/28/2/741 |
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