Azoloazines as A<sub>2a</sub> receptor antagonists. Structure – activity relationship

Саватеев, Константин В.; Ulomsky, E. N.; Butorin, Ilya I.; Charushin, Valery N.; Русинов, В. Л.; Чупахин, О. Н.

doi:10.1070/rcr4792

Cited by 29 publications

(12 citation statements)

References 67 publications

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“…It was shown previously that nitrogroup plays essential role in the azoloazine series for pronounced antiviral/antiseptic effect [7]. Considering this and structural similarity between nitro and ethoxycarbonyl fragments we synthesized a series of a new azolo[1,5a]pyrimidines 3a-l by the reaction of commercially available aminoazoles 1a-h and carbonyl-containing synthetic equivalents e.g.…”

Section: Chemistrymentioning

confidence: 99%

“…At the same time, heterocyclic derivatives of the azoloazine nature and their condensed derivatives are known for their broad range of biological activity [7]. Especially, it was shown that these compounds have a pronounced protective effect against septic shock and influenza virus in vivo [7,8]. Consequently, we consider the study of azoloazine heterocycles as potential anticoagulant agents for the treatment of cytokine storm and, in particular, DIC promising and very relevant in the modern epidemic situation.…”

Section: Introductionmentioning

confidence: 99%

“…Drugs that combine anticoagulant, antiviral and/or antibacterial activity to reduce the risk of sepsis-induced coagulopathy and arterial thromboembolism are of special interest. At the same time, heterocyclic derivatives of the azoloazine nature and their condensed derivatives are known for their broad range of biological activity [7]. Especially, it was shown that these compounds have a pronounced protective effect against septic shock and influenza virus in vivo [7,8].…”

Section: Introductionmentioning

confidence: 99%

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

Саватеев¹,

Fedotov²,

Русинов³

et al. 2021

Preprint

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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. The 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 lead compounds was confirmed using lipopolysaccharide (LPS) treated blood to mimic 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.

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Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Саватеев¹,

Fedotov²,

Русинов³

et al. 2021

Preprint

Self Cite

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“…В классе веществ, производных нитроазолоазинов, имеются соединения с разнообразной биологической активностью [19], в числе которой противовирусное [3, 10] и аденозинергическое действия [22], предотвращение септического шока [23]…”

Section: выпуск 1 (69) 2019unclassified

Antiglycation and DPP-4 Ingibition Activity of Novel Azoleazine-Derived Compounds

Sokolova¹,

Hohlacheva²,

Shamshina³

et al. 2019

Journal of Volgograd State Medical University

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В результате скрининговых исследований in vitro по поиску возможной антидиабетической активности ряда веществ, производных азолоазина, установлено, что соединения способны к умеренному ингибированию дипептидилпептидазы-4 (ДПП-4), подавляя активность фермента в среднем на 60 % в концентрации 100 мкМ, что уступает по силе действия эталонному препарату вилдаглиптину (более 99 % подавления активности ДПП-4 в той же концентрации). Также соединения способны значительно замедлять гликирование бычьего сывороточного альбумина (БСА) (лидер ряда -соединение 1в подавляет реакцию гликирования БСА на 74 % в концентрации 1 мМ, в сравнении с 58 % ингибирования для референтного соединения аминогуанидина). Способности соединений связывать (хелатировать) Cu 2+ в тесте аутоокисления аскорбиновой кислоты установить не удалось, за исключением соединения 1к (замедлял реакцию на 49 % в концентрации 40 мкМ, что сопоставимо по активности с референтным препаратом пиоглитазоном, и несколько активнее, чем липоевая кислота). Ограничение для установления медьсвязывающей активности прочих представителей ряда обусловлено высоким светопоглощением на рабочей длине волны 265 нм и не является критерием исключения хелатирующих свойств. Результаты позволяют заключить, что класс соединений является перспективной основой для дальнейшей разработки средств с антигликирующей активностью на основе структур представителей ряда.

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“…It is well known that derivatives of 1,2,4triazine-3-thione exhibit pesticide activity [1], as well as anticancer [2], psychotropic [3], and antiviral activity [4]. Annelated derivatives of triazines offer prom-ise in the field of drug development [5][6][7][8][9], in particular for neurodegenerative diseases [10]. Besides, 3-methylsulfanyl-1,2,4-triazine has been used as a base for oligomers with optoelectronic properties [11].…”

Section: Introductionmentioning

confidence: 99%

Heterocyclization of 3-Propargylsulfanyl-5 Phenyl-1,2,4-Triazine: Tandem Reactions With Bromine Leading to New Derivatives of 7 Phenyl[1,3]thiazolo[3,2-B][1,2,4]triazinium

Rybakova

Kim

Данилина

et al. 2020

IVKKT

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Derivatives of 1,2,4-triazine-3-thione exhibit biological activity in a wide range. They have optoelectronic properties and can be used as synthons in synthesis of various pyridines by the Diels-Alder reaction. 1,2,4-Triazines are of the greatest interest, for organic synthesis in particular. In the present study we have established that the interaction of 3-propargylsulfanyl-5-phenyl-1,2,4-triazine, obtained by alkylation of 5-phenyl-2,3-dihydro-1,2,4-triazine-3-thione with 3-bromopropyne in acetone in the presence of triethylamine, with halogens leads to annelation of thiazole cycle. At that, [1,3]thiazolo[3,2-b][1,2,4]triazinium systems contain either endo- or exocyclic double bond in their structure, depending on the halogen type. By way of example, iodine acting on propargyl sulfide forms a dark precipitate of (3Z)-3-iodomethylene-7-phenyl-2,3-dihydro-[1,3]thiazolo[3,2-b][1,2,4]triazinium triiodide, the structure of which has been confirmed by 1H and 13C NMR spectroscopy, including two-dimensional 2D 1H-13C HSQC, HMBC and 1H-1H NOESY experiments. Treatment of the obtained triiodide by sodium iodide in acetone leads to synthesis of the corresponding monoiodide, which precipitates from the reaction mixture as a dark red precipitate. Reaction with bromine, as distinct from heterocyclization under iodine action, comprises an unusual cascade reaction including the stages of electrophile heterocyclization, bromine addition, and hydrogen bromide elimination, which leads to formation of 3-dibromomethyl-7-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazinium bromide. It should be pointed out that the identifying feature of 3-propargylsulfanyl-5-phenyl-1,2,4-triazine heterocyclization under iodine and bromine action is the signal bias of the aromatic proton in a triazine ring towards weak field in the 1H NMR spectrum of the reaction products. This is presumably associated with formation of the positively charged nitrogen atom.

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Azoloazines as A_2a receptor antagonists. Structure – activity relationship

Cited by 29 publications

References 67 publications

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

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

Antiglycation and DPP-4 Ingibition Activity of Novel Azoleazine-Derived Compounds

Heterocyclization of 3-Propargylsulfanyl-5 Phenyl-1,2,4-Triazine: Tandem Reactions With Bromine Leading to New Derivatives of 7 Phenyl[1,3]thiazolo[3,2-B][1,2,4]triazinium

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Azoloazines as A2a receptor antagonists. Structure – activity relationship

Cited by 29 publications

References 67 publications

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

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

Antiglycation and DPP-4 Ingibition Activity of Novel Azoleazine-Derived Compounds

Heterocyclization of 3-Propargylsulfanyl-5 Phenyl-1,2,4-Triazine: Tandem Reactions With Bromine Leading to New Derivatives of 7 Phenyl[1,3]thiazolo[3,2-B][1,2,4]triazinium

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Azoloazines as A_2a receptor antagonists. Structure – activity relationship