Reconstructive Methodology in the Synthesis of 2-Aminopurine.

A fundamentally new synthetic approach to the synthesis of 2-aminopurine has been developed. It consists in the combination of the creation of a condensed polyazotic heterocyclic tetrazolopyrimidine structure, its transformation into triaminopyrimidine, and its subsequent cyclization into 2-aminopurine. The structure of the obtained compounds was established based on spectral characteristics, and the structure of the intermediate compound 5 was established directly by X-ray diffraction analysis.

4-(Aryl)-Benzo[4,5]imidazo[1,2-a]pyrimidine-3-Carbonitrile-Based Fluorophores: Povarov Reaction-Based Synthesis, Photophysical Studies, and DFT Calculations.

A series of novel 4-(aryl)-benzo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles were obtained through the Povarov (aza-Diels-Alder) and oxidation reactions, starting from benzimidazole-2-arylimines. Based on the literature data and X-ray diffraction analysis, it was discovered that during the Povarov reaction, [1,3] sigmatropic rearrangement leading to dihydrobenzimidazo[1,2-a]pyrimidines took place. The structures of all the obtained compounds were confirmed based on the data from 1H- and 13C-NMR spectroscopy, IR spectroscopy, and elemental analysis. For all the obtained compounds, their photophysical properties were studied. In all the cases, a positive emission solvatochromism with Stokes shifts from 120 to 180 nm was recorded. Aggregation-Induced Emission (AIE) has been illustrated for compound 6c using different water fractions (fw) in THF. The compounds 6c and 6f demonstrated changes in emission maxima or/and intensities after mechanical stimulation.

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.

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.

Benzimidazoazapurines: Design, Synthesis, and Photophysical Study.

A highly efficient approach to a new class of polycyclic 8-azapurines, benzo[4,5]imidazo[1,2-a][1,2,3]triazolo[4,5-e]pyrimidines (BITPs), with good photophysical characteristics is proposed. The approach comprises condensation of aminobenzimidazoles with 3-oxo-2-phenylazopropionitrile to form 3-(arylazo)benzo[4,5]imidazo[1,2-a]pyrimidine-4-amines, which undergo oxidative cyclization by the catalytic action of copper(II) acetate, resulting in BITPs with 73-84% yield. Spectral investigations demonstrated the fluorescent properties of BITPs, exhibiting good quantum yields (up to 60%) with maxima absorption at 379-399 and emission at 471-505 nm.

Pyrimido[1,2-a]benzimidazoles: synthesis and perspective of their pharmacological use.

The review presents data on the synthesis as well as studies of biological activity of new derivatives of pyrimido[1,2-a]benzimidazoles published over the last decade. The bibliography of the review includes 136 sources.

Nitrothiadiazolo[3,2-a]pyrimidines as promising antiglycating agents.

Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 µM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 µM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.