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The design of novel antagonists for adenosine A2a receptor (A2a AR) is a promising strategy for the development of new-generation anticancer agents. 5-Alkylamino-7-aminoazolo[1,5-a]pyrimidin-6-carbonitriles proposed in this work are close structural analogs of known nanomolar A2a AR antagonists. An efficient synthetic strategy towards the functional derivatives of the target heterocycles is cyclocondensation of aminoazoles with 2-[(alkylamino)(methylsulfanyl)methylene]malononitriles on heating in DMF in the presence of ButOK. The obtained azolopyrimidine-6-carbonitriles do not show statistically significant cytotoxic effect on human embryonic kidney cells, while 2-methyl- and 2-(furan-2-yl)azolopyrimidines inhibit the viability of lung carcinoma and hepatocellular carcinoma cells with IC50 values in the low micromolar range. [ABSTRACT FROM AUTHOR]

Various approaches to the synthesis of 3-halopyrazolo[1,5-a]pyrimidines were studied. It is shown that the most effective strategy consists in the construction of the azoloazine core followed by halogenation with N-iodo- or N-bromosuccinimide. A series of 3-halopyrazolo[1,5-a]pyrimidines, which are bioisosteric analogs of natural purine nucleic bases and the drug Triazavirin®, were synthesized using this strategy. The obtained compounds are interesting as precursors of novel C-nucleosides, which can be synthesized by C-C-coupling with (pseudo)ribosides containing a keto group. [ABSTRACT FROM AUTHOR]

This review is focused on the synthetic strategies to heterocyclic C-nucleosides and covers the literature from 2011 to 2021. The main attention is paid to the following three approaches: the direct C—C coupling of a carbohydrate moiety with a preformed aglycon unit, the construction of a (pseudo)sugar residue on a pre-formed aglycon, and the construction of an aglycon on a pre-formed (pseudo)sugar. In each Section, the literature data are categorized in terms of the size of aglycon from simple to complex, the advantages and drawbacks of the reviewed approaches are discussed. [ABSTRACT FROM AUTHOR]

Six compounds of the 5(7)-alkylamino-6-nitroazolopyrimidine and 8-alkylazolo[5,1-b]purine series were selected based on the structural analysis of A1 adenosine receptor inhibitors and the role of this biological target in the modulation of intraocular pressure, an important factor in the pathogenesis of glaucoma. These heterocycles were shown to exhibit a weak affinity towards the A1 adenosine receptor on an in vitro model of the adenosine-dependent change of the chronotropic effect on isolated atria of white mice. On the other hand, thiadiazolo[3,2-a]pyrimidines and triazolo[5,1-b]purine displayed an in vivo hypotensive effect in rats. The leading compound, 5-methyl-8-(hydroxyethyl)triazolo[5,1-b]purine) (0.2% solution), caused a 34% reduction of ophthalmotonus in 3 h without an adverse resorptive effect. In addition, using the MTT-test it was shown on the human HepG2 cell line that the heterocycles affecting the intraocular pressure were by one to two orders of magnitude less cytotoxic than the reference doxorubicin. [ABSTRACT FROM AUTHOR]

Nitrile-containing azoloazines with a bridged nitrogen atom are of interest as molecules with potential antiviral and antidiabetic activity. To date, a few corresponding 7-aminoazolo[1,5-a]pyrimidine-6-carbonitriles has been described in the literature and there is no universal method for their synthesis, which limits the possibility to optimize structure for preparing derivatives with prescribed biological activity. In the present work, we have studied different conditions for cyclocondensation of aminoazoles and (ethoxymethylidene)malononotrile; we have shown that optimal method for synthesis of 7-aminoazolo[1,5-a]pyrimidine-6-carbonitriles is the heating of initial components in pyridine. This method provides a library of different nitrileazolopyrimidines containing both electron-donating and electron-withdrawing substituents in the azole fragment. [ABSTRACT FROM AUTHOR]

A novel, regioselective method for the synthesis of the title compounds (VI) as structural analogues of unnatural nucleosides is developed. [ABSTRACT FROM AUTHOR]

1,2,4-Triazines with an unsubstituted (1,2,4-triazol-3-yl)amine residue in the C5 position were synthesized by the solvent-free ipso-amination reaction between 1,2,4-triazine-5-carbonitriles and 3-amino-5H- or 3-amino-5-sulfanyl-1,2,4-triazoles. In the latter case, the reaction is accompanied by desulfurization of the 1,2,4-triazole fragment. [ABSTRACT FROM AUTHOR]

The synthesis of a variety of 3-halo-2-methylpyrimidobenzimidazolones and their behavior in alkylation reactions are described. [ABSTRACT FROM AUTHOR]