Nitroazolopyrimidines – Attractive Structures in Medicinal Chemistry

We thank Russian Foundation for Basic Research (grant № 18-03-00787) for financial support

Cyanmorpholinoethylene in the synthesis of relevant azoloazines

Approach to the synthesis of promising azolopyrimidines containing a primary amino group by reactions of variously substituted aminoazoles with cyanmorpholinoethylene was developed. © 2019 Author(s)

Cyanmorpholinoethylene in the Synthesis of Relevant Azoloazines

The results were obtained within the framework of the state task of the Ministry of education and science of Russia (4.6351.2017/8.9) and with the financial support of the Russian science Foundation (№ 17-13-01096)

Atom-efficient synthesis of hybrid molecules combining fragments of triazolopyrimidines and 3-ethoxycarbonyl-1-ethyl-6-fluoroquinolin-4(1H)-one through 1,2,3-triazole linker

[Figure not available: see fulltext.] An atom-efficient method toward hybrid molecules via azide-alkyne cycloaddition of 7-azido-3-ethoxycarbonyl-1-ethyl-6-fluoroquinolin-4(1H)-one and novel perspective triazolopyrimidines has been developed. This procedure features mild conditions and a broad substrate scope including hydrophobic and hydrophilic triazolopyrimidines. The synthesized hybrid structures combine fragments of fluoroquinolone with proved antibacterial activity and triazolopyrimidines, which may act as structural analogs of adenosine receptor effectors or antiviral azoloazine heterocycles. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.Russian Foundation for Basic Research, РФФИ: 18-03-00787 АWe wish to thank the Russian Foundation for Basic Research for financial support (grant 18-03-00787 А)

Azoloazines as Perspective Antiglycating Agents for Therapy of Diabetes Complications

This work was supported by Russian Federation Ministry of education and science (grant № 4.6351.2017/8.9) and Russian Foundation for Basic Research (grant № 18-03-00787)

6-Aminotriazolo[1,5-a]pyrimidines as precursors of 1,2,4-triazolo[5,1-b]purines

Triazolo[5,1-b]purines are rare structural analogues of natural nucleosides and nucleobases purine series. At the same time, prominent representatives of azolopurines exhibit a broad spectrum of antiviral effect, activity against of rheumatoid arthritis, psoriasis, Alzheimer’s, Parkinson’s and etc. Despite the practical value azolo[5,1-b]purines extremely sparingly represented in the chemical literature, due to the complexity of their synthesis. We suggest a convenient way to synthesize triazolopurines with aminotriazolo[1,5-a]pyrimidines (2) as available starting compounds obtained in good yield by reduction of nitro derivatives (1).The work was supported by RFBR grant 13-03-0086

Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Funding: This research was funded within the framework of the grant agreement as government subsidies from the federal budget in accordance with paragraph 4 of article 78.1 of the Budget Code of the Russian Federation (Moscow, 1 October 2020, No. 075-15-2020-777)

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

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. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Ministry of Education and Science of the Russian Federation, Minobrnauka: 075-15-2020-777Funding: This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement on the provision of grants from the federal budget in the form of subsidies under paragraph 4 of Article 78.1 of the Budget Code of the Russian Federation, Moscow, 1 October 2020 No. 075-15-2020-777)

Searching for novel antagonists of adenosine A1 receptors among azolo[1,5-a]pyrimidine nitro derivatives

Introduction: Ligands of adenosine A1Rs are potential candidates for the development of drugs for the treatment of paroxysmal supraventricular tachycardia, angina pectoris, hypertriglyceridemia, type 2 diabetes mellitus, neuropathic pain, and heart failure. At the same time, there is a deficiency of drugs that can regulate the functions of A1 receptors. A number of A1-antagonists are at the various stages of clinical trials; other drugs are not very selective or are characterized by an insufficient breadth of their therapeutic action. Therefore, the search for new medicinal compounds for the prevention and treatment of A1-depended diseases among nitro derivatives of tetrazolo[1,5-a]pyrimidine and 1,2,4-triazolo[1,5-a]pyrimidine is of scientific interest. Materials and methods: The search for active compounds was carried out by in silico and in vitro methods. At the first stage, a computer forecast of A1-antagonistic activity was carried out using the Microcosm BioS software. At the second stage, the prediction results were verified in vitro in a model of isolated mouse atria. Results and discussion: Based on the results of the prediction by the method of maximum similarity to standards, the most active compounds III, VIII, and XVII were selected. After testing the prediction results by the isolated atria method, the compound VIII was characterized by A1-blocking effect in vitro at a concentration of 10 μmol/L. Conclusion: The most promising compound with A1-blocking effect in vitro was identified; it is a derivative of tetrazolo[1,5-a]pyrimidine under the code of VIII. It is of interest for us for further in-depth study of its pharmacological properties. Copyright Yakovlev DS et al.The reported study was partially funded by the Gover

New antiglycating agents for diabetes therapy

It was shown that azoloazines (1) demonstrated higher antiglycation activity than reference compound, aminoguanidine, and have some potential as dipeptidylpeptidase-4 inhibitors. By given results this class of heterocycles can be considered as candidate for extended studies to develop drugs against complications of T2DM [1-4].The work was supported by the Ministry of Education and Science of Russia (grant №0836-2020-0058)