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

• Main Authors: Alexander Spasov (Author), Vadim Kosolapov (Author), Denis Babkov (Author), Vladlen Klochkov (Author), Elena Sokolova (Author), Mikhail Miroshnikov (Author), Alexander Borisov (Author), Yulia Velikorodnaya (Author), Alexey Smirnov (Author), Konstantin Savateev (Author), Victor Fedotov (Author), Svetlana Kotovskaya (Author), Vladimir Rusinov (Author)
• Format: Book
• Published: MDPI AG, 2022-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 <b>9g</b> 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. <b>9g</b> ameliorated anxiety-like behavior, inhibited IL-6 release, and limited neutrophil infiltration and pulmonary edema. A histological study confirmed the protective activity of <b>9g</b>. Treatment with compound <b>9g</b> 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.

Item Description

10.3390/ph15050537
1424-8247