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Article

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

1
Department of Pharmacology & Bioinformatics, Scientific Center for Innovative Drugs, Volgograd State Medical University, Volgograd 400131, Russia
2
Department of Organic and Biomolecular Chemistry, Ural Federal University Named after the First President of Russia B.N. Yeltsin, Mira Street, 19, Yekaterinburg 620002, Russia
*
Author to whom correspondence should be addressed.
Academic Editors: Thierry Besson and Pascal Marchand
Pharmaceuticals 2022, 15(5), 537; https://doi.org/10.3390/ph15050537
Received: 18 March 2022 / Revised: 19 April 2022 / Accepted: 22 April 2022 / Published: 27 April 2022
(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)
Acute lung injury remains a challenging clinical condition, necessitating the development of novel, safe and efficient treatments. The prevention of macrophage M1-polarization is a viable venue to tackle excessive inflammation. We performed a phenotypic screening campaign to identify azolopyrimidine compounds that effectively inhibit LPS-induced NO synthesis and interleukin 6 (IL-6) secretion. We identified lead compound 9g that inhibits IL-6 secretion with IC50 of 3.72 µM without apparent cytotoxicity and with minimal suppression of macrophage phagocytosis in contrast to dexamethasone. In a mouse model of LPS-induced acute lung injury, 30 mg/kg i.p. 9g ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of 9g. Treatment with compound 9g prevented the migration of CD68+ macrophages and the incidence of hemorrhage. Hence, we have identified a promising pharmacological approach for the treatment of acute lung injury that may hold promise for the development of novel drugs against cytokine-mediated complications of bacterial and viral infections. View Full-Text
Keywords: cytokine; IL-6; inflammation; acute lung injury; macrophage; azolo[1,5-a]pyrimidines cytokine; IL-6; inflammation; acute lung injury; macrophage; azolo[1,5-a]pyrimidines
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MDPI and ACS Style

Spasov, A.; Kosolapov, V.; Babkov, D.; Klochkov, V.; Sokolova, E.; Miroshnikov, M.; Borisov, A.; Velikorodnaya, Y.; Smirnov, A.; Savateev, K.; Fedotov, V.; Kotovskaya, S.; Rusinov, V. Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury. Pharmaceuticals 2022, 15, 537. https://doi.org/10.3390/ph15050537

AMA Style

Spasov A, Kosolapov V, Babkov D, Klochkov V, Sokolova E, Miroshnikov M, Borisov A, Velikorodnaya Y, Smirnov A, Savateev K, Fedotov V, Kotovskaya S, Rusinov V. Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury. Pharmaceuticals. 2022; 15(5):537. https://doi.org/10.3390/ph15050537

Chicago/Turabian Style

Spasov, Alexander, Vadim Kosolapov, Denis Babkov, Vladlen Klochkov, Elena Sokolova, Mikhail Miroshnikov, Alexander Borisov, Yulia Velikorodnaya, Alexey Smirnov, Konstantin Savateev, Victor Fedotov, Svetlana Kotovskaya, and Vladimir Rusinov. 2022. "Discovery of Nitro-azolo[1,5-a]pyrimidines with Anti-Inflammatory and Protective Activity against LPS-Induced Acute Lung Injury" Pharmaceuticals 15, no. 5: 537. https://doi.org/10.3390/ph15050537

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