Synthesis and cytotoxic activity of (2-arylquinazolin-4-yl)hydrazones of 2-hydroxybenzaldehydes

2-Phenyl-6,7-difluoro and 2-(4-fluorophenyl)quinazoline derivatives bearing salicylidenhydrazino fragments at position 4 were prepared based on 4,5-difluoroantranilic acid or anthranilamide. Molecular docking to casein kinase 2 was performed; compounds with high in silico activity to CK2 were revealed. Cytotoxic activity of the synthesized compounds was studied on cancer cell line MDA-MB-231 and normal cell line WI26 VA4

6-(Tetrazol-5-yl)-7-aminoazolo[1,5-<i>a</i>]pyrimidines as Novel Potent CK2 Inhibitors

In this work, we describe the design, synthesis, and structure-activity relationship of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-a]pyrimidines as inhibitors of Casein kinase 2 (CK2). At first, we optimized the reaction conditions for the azide-nitrile cycloaddition in the series of 6-cyano-7-aminoazolopyridimines and sodium azide. The regioselectivity of this process has been shown, as the cyano group of the pyrimidine cycle was converted to tetrazole while the nitrile of the azole fragment did not react. The desired tetrazolyl-azolopyrimidines were obtained in a moderate to excellent yields (42–95%) and converted further to water soluble sodium salts by the action of sodium bicarbonate. The obtained 6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidines 2a–k and their sodium salts 3a–c, 3g–k showed nano to low micromolar range of CK2 inhibition while corresponding [1,2,4]triazolopyrimidines 10a–k were less active (IC50 > 10 µM). The leader compound 3-phenyl-6-(tetrazol-5-yl)-7-aminopyrazolo[1,5-a]pyrimidine 2i as CK2 inhibitor showed IC50 45 nM

Chemo-Enzymatic Synthesis and Biological Evaluation of 5,6-Disubstituted Benzimidazole Ribo- and 2 '-Deoxyribonucleosides

A number of new 5,6-disubstituted benzimidazoles have been prepared and their substrate properties for recombinant E. coli purine nucleoside phosphorylase (PNP; the product of the deoD gene) in the transglycosylation reaction were investigated. The heterocyclic bases showed good substrate activity for PNP and the ribo- and 2-deoxyribonucleosides were synthesized. The predominant (OMe and OEt) or exclusive (Oi-Pr, morpholino, and N-methylpiperazino) formation of the 5-substituted 6-fluoro-1-(β-d- ribofuranosyl)benzimidazoles was observed. The formation of the regioisomeric 6- methoxy-, 6-ethoxy-, or 6-isopropoxy-substituted 1-(2-deoxy-β-d- ribofuranosyl)-5-fluorobenzimidazoles was observed in the trans-2- deoxyribosylation reaction of the corresponding bases. The predominant or exclusive formation of the regioisomeric N1-nucleosides with bulky 5-substituents of 6-fluorobenzimidazole points to a large hydrophobic pocket in the E. coli PNP active site that can accommodate these groups. The biological activity of the synthesized nucleosides was studied and revealed no inhibitory activity against a broad variety of DNA and RNA viruses. The compounds also lacked significant cytotoxicity. © Georg Thieme Verlag Stuttgart New York.status: publishe

Azolo[1,5-<i>a</i>]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