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)

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)

Fluorinated Derivatives of Benz[4,5]imidazo[1,2-b][1,3] thiazole - Inhibitors of Reproduction of Measles Virus

ACKNOWLEDGMENTS This study was supported by MNTTs (grant no. 1198), Russian Foundation for Basic Research (project no. 03-03-32254), the Ministry of Education of the Russian Federation, and the American Civil Research and Development Foundation (CDRF, grants REC-005 and EK-005-XI)

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)

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)

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)

New heterocyclic compounds of the azolopyrimidine series with pronounced antitumor activity

The purpose of the study was to study the effect of new azolopyrimidine compounds on the viability of cultured tumor cells and to identify promising compounds for the development of new antitumor drugs.Цель исследования – изучение влияния новых азолопиримидиновых соединений на жизнеспособность культивируемых опухолевых клеток и выявление перспективных соединений для разработки новых противоопухолевых препаратов

CK2 Inhibition and Antitumor Activity of 4,7-Dihydro-6-nitroazolo[1,5-a]pyrimidines

Today, cancer is one of the most widespread and dangerous human diseases with a high mortality rate. Nevertheless, the search and application of new low-toxic and effective drugs, combined with the timely diagnosis of diseases, makes it possible to cure most types of tumors at an early stage. In this work, the range of new polysubstituted 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines was extended. The structure of all the obtained compounds was confirmed by the data of 1H, 13C NMR spectroscopy, IR spectroscopy, and elemental analysis. These compounds were evaluated against human recombinant CK2 using the ADP-GloTM assay. In addition, the IC50 parameters were calculated based on the results of the MTT test against glioblastoma (A-172), embryonic rhabdomyosarcoma (Rd), osteosarcoma (Hos), and human embryonic kidney (Hek-293) cells. Compounds 5f, 5h, and 5k showed a CK2 inhibitory activity close to the reference molecule (staurosporine). The most potential compound in the MTT test was 5m with an IC50 from 13 to 27 µM. Thus, our results demonstrate that 4,7-dihydro-6-nitroazolo[1,5-a]pyrimidines are promising for further investigation of their antitumor properties. © 2022 by the authors.Ministry of Education and Science of the Russian Federation, Minobrnauka: FEUZ-2020–0058, H687.42B.223/20This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation, State Contract № FEUZ-2020–0058 (H687.42B.223/20)

Diagnosis and Treatment of Elderly and Senile Chronic Constipation: an Expert Consensus

Aim. An appraisal of practitioners with chronic constipation management details in older and senile adults.Key points. Chronic constipation is a common issue in geriatrics. Aside to age-related physiological bowel disfunction, a higher constipation incidence is conditioned by declined physical activity and frailty, polypharmacy and a series of secondary constipation-developing chronic states and diseases. Chronic constipation is associated with a higher risk of cardiovascular disease and complications, impaired general perception of health and pain, growing alarm and depression, and reduced quality of life. The treatment tactics in chronic constipation is cause-conditioned and should account for the patient’s history and therapy line, overall clinical condition, cognitive status and functional activity level. An essential baseline aspect of constipation management is apprising the patient and his family of the underlying factors and methods for non-drug and drug correction. An higher-fibre diet is recommended as first measure, with osmotic laxatives added and titrated to clinical response if none observed towards the non-drug and high-fibre regimens. Stimulant laxatives and prokinetics should be recommended in patients reluctant to fibre supplements and osmotic laxatives. Subsidiary correction includes biofeedback, transanal irrigation, acupuncture, foot reflexology and percutaneous tibial nerve stimulation.Conclusion. Elderly and senile chronic constipation is a prevalent multifactorial state requiring an efficient management via assessment and correction of total risk factors and consistent use of non-medication and drug therapies

Clinical Practice Guidelines of the Russian Scientific Liver Society, Russian Gastroenterological Association, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians and National Society for Preventive Cardiology on Diagnosis and Treatment of Non-Alcoholic Liver Disease

Aim: present clinical guidelines, aimed at general practitioners, gastroenterologists, cardiologists, endocrinologists, comprise up-to-date methods of diagnosis and treatment of non-alcoholic fatty liver disease.Key points. Nonalcoholic fatty liver disease, the most wide-spread chronic liver disease, is characterized by accumulation of fat by more than 5 % of hepatocytes and presented by two histological forms: steatosis and nonalcoholic steatohepatitis. Clinical guidelines provide current views on pathogenesis of nonalcoholic fatty liver disease as a multisystem disease, methods of invasive and noninvasive diagnosis of steatosis and liver fibrosis, principles of nondrug treatment and pharmacotherapy of nonalcoholic fatty liver disease and associated conditions. Complications of nonalcoholic fatty liver disease include aggravation of cardiometabolic risks, development of hepatocellular cancer, progression of liver fibrosis to cirrhotic stage.Conclusion. Progression of liver disease can be avoided, cardiometabolic risks can be reduced and patients' prognosis — improved by the timely recognition of diagnosis of nonalcoholic fatty liver disease and associated comorbidities and competent multidisciplinary management of these patients