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Background. The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, originated in Wuhan, China, has claimed millions of lives around the world. In this regard, the search for effective drugs, including the repurposing of existing ones, has become an urgent task. A promising treatment strategy appears to be drug disruption of viral reproduction. RNA-dependent RNA polymerase (RdRp) is the central subunit of the RNA synthesis process for all positive-strand RNA viruses and is therefore an attractive target for antiviral inhibitors.The aim of this work is an experimental study of the antiviral activity of various drugs based on 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (Favipiravir) in vitro and in vivo against the SARS-CoV-2 coronavirus (COVID-19).Material and methods. The experiments were carried out on a permanent culture of African green monkey kidney cells — Vero Cl008. The effectiveness of the drugs was assessed by suppressing the reproduction of the virus in vitro. Biological activity was assessed by titration of the virus-containing suspension in Vero Cl008 cell culture by the formation of negative colonies. Syrian golden hamsters orally infected with the SARS-CoV-2 virus, variant B, were used in the study. The effectiveness of the drug was assessed by the coefficient of therapeutic action.Results. The results of the study revealed that the compounds FP-1 and Avifavir in the concentration range of 100–400 µg/ml almost completely suppress the reproduction of the SARS-CoV-2 virus; the CTI index for the drug FP-1 was 4, for Avifavir it was 2. The ED₅₀ value for FP-1 was 26 µg/ml, for Avifavir it was 36 µg/ml. Preparations T-705 and Coronavir revealed antiviral activity only at extremely high concentrations. The CTI was 1. During the study on Syrian golden hamsters orally infected with the SARS-CoV-2 virus, variant B, at a dose of 5×105 PFU, it was shown that the use of Avifavir and FP-1 has a high protective efficacy, while Coronavir and T-705 cause a moderate suppression of virus reproduction in the target organ. According to the complex of clinical-virological, biochemical, and hematological indicators, the disease severity index (DSI) and the therapeutic index (TI) were calculated. For the drug Avifavir, the DSI was 0.269; the TI was 71.3% with a probability of 99.9%.Conclusion. Of the studied compounds, Avifavir and FP-1 showed the highest antiviral activity.

Convenient methods for the synthesis of three monomers based on functionalized (bi)pyridines with using “1,2,4-triaizine” methodology have been developed.

A convenient synthesis of 1,2,4-triazines bearing the moieties of (hetero)arylhydrazines at the position of C5 of the 1,2,4-triazine core is reported.

An efficient synthetic approach towards 5-arylethynyl-1,2,4-triazines via direct C-H-functionalization of 5-H-1,2,4-triazines in reaction with lithium acetylenes is reported.

The experimental study of the prophylactic efficacy of Triazaverin against the experimental form of the influenza virus A (H5N1) on albino mice intranasally infected with the influenza virus A/Chicken/Kurgan/Russia/02/05 vs. the reference drugs Tamiflu®, Remantadin and Arbidol® showed that in doses of 1 to 100 mg/kg it was efficient in the animal protection from death. The drug was also efficient in the urgent prophylaxis. Triazaverin effectively inhibited the influenza A virus multiplication in the lungs of the albino mice.

Therapeutic activity of Triazavirin against experimental influenza A was studied on albino mice intranazally infected with influenza virus A/Chicken/Kurgan/Russia/02/05 (H5N1) vs. reference drugs (Oseltamivir, Remantadin and Arbidol®). The study showed that in a therapeutic dose of 1 mg/kg Triazavirin was efficient in protection of the animals from death. Its protective therapeutic efficacy (36.7+1.7%) was close to that of Oseltamivir (50.0+0.0%), comparable with that of Remantadin (38.3+1.7%) and higher than that of Arbidol® (11.7+1.7%). During the whole observation period (up to the terminal phase) Triazavirin inhibited the influenza virus A accumulation in the lungs of the infected albino mice by more than 3 lg.

The study of the toxicity of triazavirin, a new antiinfluenza agent, showed that the maximum concentration of the drug, inducing no microscopically visible changes in the structure of the monolayer and the cells of the MDCK and SKEV cell cultures, was 128 and 100 mcg/ml respectively. The maximum drug dose for single intraperitoneal administration inducing no signs of acute intoxication in albino mice weighing 10-12 g was 1000 mg/kg. In investigation of the chronic toxicity it was shown that oral administration of the drug (by 0.05 ml) to the albino mice in a dose of 200 mg/kg (maximum possible concentration by the solubility) daily for 10 days was well tolerated by the laboratory animals. The maximum tolerable dose of triazavirin for the albino mice was ≥200 mg/kg.

The efficacy of Triazavirin against the tick-borne encephalitis virus was estimated in the sensitive cell culture vs. the active drug Ribavirin®. In a concentration of 128 mcg/ml Triazavirin was shown active in inhibition of the tick-borne encephalitis virus reproduction (strain Sofiin) by accumulation in the SKEV cell culture.

The comparative study of the therapeutic efficacy of Triazavirin against experimental Forest-Spring encephalitis on albino mice vs. the active drug Ribavirin® showed that in high doses (200-400 mg/kg) Triazavirin moderately protected the infected animals. A significant increase of the animal lifespan in the test groups (from 4.1 to 4.8 days) and a statistically (p

A procedure for the simantenous determination of aminotriazole, triazolopyrimidinone and nirotriazolopyrimidinone was developed using the HPLC method with UV detection. To achieve the best chromatographic characteristics, it is proposed to use a column with a grafted aminophase Zorbax NH2 (Agilent Technologies, USA). The possibility of applying the developed methodology for the technological control of the second stage of the drug «Triazid» preparation is established following the results of the validation.

Method of simultaneous determination of aminotriazole and triazolopyrimidinone using HPLC with UV-detection was developed. For best chromatographic performance Zorbax NH2 amino phase column (Agilent Technologies, USA) was selected. The applicability of the developed method for providing technological control of the 1st stage of «Triazide» production was approved according to the results of validation procedure.

The paper contains а results of the study of the pharmacokinetics, tolerability and safety of a new influenza drug Triazide in several dose regimens conducted on healthy volunteers. The convenient method for the determining the Triazide in blood plasma and urine by the HPLC have been proposed for the using in this study. There was no reliable statistical relationship between drug intake, undesirable clinical events and changes in laboratory parameters. A study of the pharmacokinetics have been showed that Triazide in the blood plasma was found on average after 0.5 hours, the curve of decrease in concentrations was two-phase, the half-life in the first phase was 1.5-4.0 hours. The maximum concentrations with increasing dose increased in direct proportion. With an increase in the daily dose, the maximum concentration was reached earlier. At the same time, no significant cumulation was observed with prolonged use. In the study, Triazide was well tolerated by all participants in all studied dose regimens. Preferred regimens that provide maintenance of effective and safe concentrations, appearances were 300 mg two and three times a day.

A procedure for quantitative determination of 5-methyl-6-nitro-7-oxo-1,2,4-triazolo[1,5-a]pirimidinide l -argininy was developed using the HPLC method with UV detection. To achieve the best chromatographic characteristics, it is proposed to use a column with a grafted octadecylsilyl phase 5-100-c18 (EKA, Sweden). The possibility of applying the developed procedure for the technological control of the third stage of the drug «Triazid» preparation was proved by the validation.

Two ethyleneglycol esters of 1-pyrene carboxylic acid were studied as chemosensors for the fluorescence “turn-off” detection of two nitro-containing analytes, such as antiviral drug Riamilovir (Triazavirin ®) and herbicidal agent dinitro-ortho-cresol (DNOC). In both cases the dramatic fluorescence quenching was observed with quenching constants as high as 3·104 M-1 and limits of detection (LOD) as low as 100 ppb.

Prophylactic efficacy of Triazavirin against experimental Forest-Spring encephalitis was studied on albino mice vs. the active drug Ribavirin®. A significant increase of the animal lifespan in the test groups (from 4 to 5 days) and a statistically (р

A convenient method for the obtaining of 3,6-diaryl-1,2,4-triazines substituted with residues of higher alcohols in the position of C5 via the ipso-substitution of cyano group in under the solvent free conditions was reported. This method indicates a new example for the functionalization of the 1,2,4-triazines via the substitution of the cyano group.

Two mutually complementary synthetic approaches towards 3- and 3,4-disubstituted 1-(2-pyridyl) isoquinolines were studied. The aryne-based method was successfully used for the obtaining of the corresponding the 3-cyano-1-(2-pyridyl)isoquinolines in one step/pot reaction, while it is unacceptable for the obtaining of other 1-(2-pyridyl)isoquinolines. The enamine-based approach was successfully applied for the synthesis of other 1-(2-pyridyl)isoquinolines, while it was unacceptable for the obtaining of 3-cyano-1-(2-pyridyl)isoquinolines.

As a model of metabolic transformations of antiviral drug “Triazaverin” and its analogues‑2-alkylthio‑6-nitro‑1,2,4-triazolo[5,1-c][1,2,4]triazine‑7-ones 1a-d examined the oxidation of alkylthio groups to the corresponding sulfoxides 2a-d and sulfones 3a-d, as well as the process of nucleophilic substitution sulfonyloxy group of cysteine and cysteamine with the formation of compounds 5 and 6.

Triazolo[5,1-b]purines are rare structural analogues of natural nucleosides and nucleobases purine series. At the same time, prominent representatives of azolopurines exhibit a broad spectrum of antiviral effect, activity against of rheumatoid arthritis, psoriasis, Alzheimer's, Parkinson's and etc. Despite the practical value azolo[5,1-b]purines extremely sparingly represented in the chemical literature, due to the complexity of their synthesis. We suggest a convenient way to synthesize triazolopurines with aminotriazolo[1,5-a]pyrimidines (2) as available starting compounds obtained in good yield by reduction of nitro derivatives (1).

New analogues of acyclovir have been prepared by reacting 1,2,4-triazolo[1,5-a]pyrimidin-7-ones 1а-i and (2-acetoxyethoxy)methyl acetate 2 in the presence of trimethylsilyl trifluoromethanesulfonate as a catalyst. Thei nteraction between the compounds 1а-е and 2 has led to a mixture of N3 and N4 isomers. In contrast, the reaction of compounds 1g-i and 2 proceeded selectively to form N3 isomers. In the case of compounds 1a-c the predominant product is the one with the acyclic moiety in azine ring (N4 isomer). Interaction between 1d-f and 2 has led to mixtures comprising mainly N3 isomer. It has been found that the ratio of glycosylation products 1 and 2 are thermodynamically controlled. The structure of the obtained compounds has been proved by 1Н, 13С, two-dimensional 1Н-13С NMR spectroscopy and X-ray analysis.

A simple procedure was developed for the synthesis of 1,2,4-triazines and their 4-oxides containing the ClCH2, Cl2CH, or CCl3 group at position 3 by cyclization of 2-aryl-2-hydrazono-1-oximinoethanes with the corresponding chloroacetonitriles. The reaction pathway depends on the number of halogen atoms in the acetonitrile used. The reactions with trichloroacetonitrile, monochloroacetonitrile, and dichloroacetonitrile afford 3-trichloromethyl-1,2,4-triazines, 3-chloromethyl-1,2,4-triazine 4-oxides, and a mixture of the corresponding dichloromethyltriazines and their 4-oxides, respectively. The reactions of 3-trichloromethyl-1,2,4-triazines with indoles and phenols are accompanied by tele-substitution with elimination of halogen from the trichloromethyl group to give 5-indolyl- (or 5-hydroxyphenyl)-3-dichloromethyl-1,2,4-triazines. [ABSTRACT FROM AUTHOR]

The reaction of 3-phenyl-1,2,4-triazin-5(4H)-one (1) with l-menthol in the presence of aliphatic acid anhydrides results in (6S)- and (6R)-1-acyl-6-(l-menth-3-yl)-1,6-dyhydro-3-phenyl-1,2,4-triazin-5(4H)-ones. The reaction is diastereoselective with predominant formation of (6S)-isomers. The reaction diastereoselectivity increases with enhancement of the steric hindrance in the vicinity of the reaction center of the azine. [ABSTRACT FROM AUTHOR]

The reactions of 1-lithia-1,2- or 1,7-dicarba-closo-dodecaborane with 1,2,4-triazine 4-oxides can follow two competitive pathways: deoxygenative nucleophilic substitution of hydrogen to form 1-(1,2,4-triazin-5-yl)-1,2- or 1,7-dicarba-closo-dodecaboranes and the transformation of the 1,2,4-triazine ring into the triazoline ring giving rise to 1-(2-acetyl-1-aroyl-3-aryl-1,2,4-triazolin-5-yl)-1,2-dicarba-closo-dodecaboranes. Introduction of the electron-withdrawing triazine ring into the carborane cage substantially facilitates deboronation to give 1-(1,2,4-triazin-5-yl)-1,2-1,7-dicarba-nido-undecaboranes. [ABSTRACT FROM AUTHOR]

Nucleophilic substitution of hydrogen in pyrazine N-oxides under the action of CH-active compounds requires activation with acylating agents. This activation facilitates aromatization of intermediate σH adducts via elimination of the acid residue to form substituted pyrazines. More electrophilic 1,2,4-triazine 4-oxides react with carbanions derived from CH-active compounds without additional activation according to a scheme, which has previously been unknown for azine N-oxides. This scheme involves aromatization of σH adducts through elimination of water by the E1cb mechanism. The reaction products occur in DMSO-d6 solutions predominantly as 6-methylene-1,6-dihydropyrazines and 5-methylene-4,5-dihydro-1,2,4-triazines. [ABSTRACT FROM AUTHOR]

Pyrimidine 1-oxides with cyanamide afforded 2-ureidopyrimidines as the result of the nucleophilic substitution of hydrogen, whereas the formation of similar 2-trichloroacetylaminopyrimidines occurs as dipolar 1,3-cycloaddition of the same oxides to trichloroacetonitrile under much more drastic conditions and in lower yields. [ABSTRACT FROM AUTHOR]