Synthesis of isomeric 4-(N-methyltetrazolylamino)-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehydes and 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde based on tandem thiol-Michael and (aza)-Morita-Baylis-Hillman reactions and an in vitro study of the activity of the obtained compounds against influenza virus.

3-{[(1-Methyl-1H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol and 3-{[(2-methyl-2H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol were synthesized. The sequence of the thiol-Michael reaction and the (aza)-Morita-Baylis-Hillman reaction yielded 4-[(1-methyl-1H-tetrazol-5-yl)amino]-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde, 4-[(2-methyl-2H-tetrazol-5-yl)amino]-2-phenyl-4H-thiopyrano[2,3-b]-quinoline-3-carbaldehyde, and 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde. Cytotoxicity and antiviral activity against the A/Puerto Rico/8/34 (H1N1) influenza virus strain in MDCK cell culture were determined for the obtained compounds. The study showed that the replacement of the hydroxyl group in 4-hydroxy-2-phenyl-4H-thiopyrano[2,3-b]quinoline-3-carbaldehyde with a 1-methyl- or 5-amino-2-methyltetrazolyl fragment decreased antiviral activity. At the same time, 3-{[(1-methyl-1H-tetrazol-5-yl)imino]-methyl}quinoline-2-thiol has a higher activity than 3-{[(2-methyl-2H-tetrazol-5-yl)imino]methyl}quinoline-2-thiol. This fact indicates a possible relationship between the arrangement of substituents in the tetrazole ring and the antiviral activity of the tested heterocyclic system. Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-022-03083-w.

Synthesis, structure, and antiviral properties of novel 2-adamantyl-5-aryl-2H-tetrazoles.

The reaction of 5-aryl-NH-tetrazoles with adamantan-1-ol in concentrated sulfuric acid proceeds regioselectively with the formation of the corresponding 2-adamantyl-5-aryl-2H-tetrazoles. Nitration of these compounds leads to 2-(adamantan-1-yl)-5-(3-nitroaryl)-2Htetrazoles. The structures and composition of the obtained novel 2-adamantyl-5-aryltetrazoles were proven by IR spectroscopy, 1H and 13C NMR spectroscopy, high-resolution mass spectrometry, and also by X-ray structural analysis. According to the simultaneous thermal analysis data, the obtained compounds are thermally stable up to a temperature of about 150°C. In vitro studies have shown that some of the 2-adamantyl-5-aryltetrazoles exhibit moderate inhibitory activity against influenza A (H1N1) virus. The antiviral selectivity index (SI) of 2-[2-(adamantan-1-yl)-2H-tetrazol-5-yl]-6-bromo-4-nitroaniline is significantly higher (SI 11) than that of the reference drug rimantadine (SI 5). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10593-021-02931-5.

Synthesis and antiviral activity of nonannulated tetrazolylpyrimidines.

Nonannulated tetrazolylpyrimidines in the structure of which the heterocyclic fragments are separated by hydrazinocarbonylmethyl, methylpyrazolyl groups or a sulfur atom were synthesized. Some of these compounds showed moderate in vitro activity against H1N1 subtype of influenza A virus. The selectivity index of the anti-influenza action of {5-[(4,6-dimethylpyrimidin-2-yl)sulfanyl]-1H-tetrazol-1-yl}acetic acid, which has very low cytotoxicity, was twice as high as the selectivity index of the reference drug rimantadine.

Methods of Synthesis and Antiviral Activity of New 4-Alkyl-3-Nitro-1,4-Dihydroazolo[5,1-c][1,2,4]Triazin-4-ols.

An azo coupling reaction of α-nitro ketones with 5-diazoazoles was used to obtain 4-alkyl-3-nitro-1,4-dihydroazolo[5,1-с][1,2,4]triazines, which were characterized with respect to their antiviral activity against influenza and Coxsackie B3 viruses. Supplementary Information: The online version contains supplementary material available at 10.1007/s10593-021-02926-2.

7-Imidazolyl-substituted 4'-methoxy and 3',4'-dimethoxy-containing polyfluoroflavones as promising antiviral agents.

A simple and convenient method for the synthesis of new methyl 2-(4-methoxyphenyl)- and 2-(3,4-dimethoxyphenyl)-4-oxo-4H-polyfluorochromen-3-carboxylates as analogs of natural methoxy-containing flavones is proposed. As a result of their directed modification under basic conditions, 7-imidazolyl-substituted derivatives were obtained. In aqueous-organic medium under basic conditions, 5,6,7,8-tetrafluoro-3-(methoxycarbonyl)flavones were transformed into 6,8-difluoro-5-hydroxy-7-(1H-imidazol-1-yl)-3-(methoxycarbonyl)flavones as a result of flavone-5-hydroxyflavone rearrangement, while 6,7,8-trifluorinated analogs underwent a flavone-coumarin rearrangement to give 6,8-difluoro-3-(hydroxyarylidene)-7-(1H-imidazol-1-yl)coumarins under the same conditions. Acid hydrolysis of methyl polyfluoroflavone-3-carboxylates allowed to obtain 2-aryl-4H-polyfluorochromen-4-ones. Evaluation of the antiviral activity of the synthesized compounds against influenza A (H1N1) and Coxsackie B3 viruses showed that 2-(3,4-dimethoxyphenyl)-5,6,8-trifluoro-7-(1H-imidazol-1-yl)-4H-chromene-4-one has the most promising properties.

Single-stage synthesis of heterocyclic alkaloid-like compounds from (+)-camphoric acid and their antiviral activity.

An effective technique for one-stage synthesis of new polycyclic nitrogen-containing compounds has been developed. The procedure involves refluxing mixtures of camphoric acid with aliphatic or aromatic diamine without catalysts. In cases where the starting amine has a low boiling point (less than 200 °C), phenol is used as a solvent, as it is the most optimal one for obtaining products with good yields. It has been shown that the use of Lewis acids as catalysts reduces the yield of the reaction products. A set of compounds have been synthesized, which can be attributed to synthetic analogues of alkaloids. In vitro screening for activity influenza virus A was carried out for the obtained compounds. The synthesized quinazoline-like agent 14 has inhibitory activity against different strains of influenza viruses.

5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines as dual inhibitors of Mycobacterium tuberculosis and influenza virus: Synthesis and evaluation.

This study describes synthesis and evaluation of novel 5-Chloro-2-thiophenyl-1,2,3-triazolylmethyldihydroquinolines 7a-o as dual inhibitors of Mycobacterium tuberculosis and influenza virus. Huisgen's [3+2] dipolar cycloaddition of 6-(azidomethyl)-5-chloro-2-(thiophen-2-yl)-7,8-dihydroquinoline 5 with various alkynes 6a-o using sodium ascorbate and copper sulphate gave new dihydroquinoline-1,2,3-triazoles 7a-o in good to excellent yields. The new compounds were evaluated for in vitro antimycobacterial against M. tuberculosis H37Rv (Mtb) and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1). Among the fifteen new analogs, compounds 7a (MIC: 3.12 µg/mL), 7j and 7k (MIC: 6.25 µg/mL) were identified as potent antitubercular agents. The virus-inhibiting activity of all the fifteen compounds was found to be moderate, and among them the compound 7l, bearing thiophene moiety appeared the most active with good selectivity index (IC50 = 19.5 µg/mL; SI = 15). The results presented here will help developing newer dual inhibitors of tuberculosis and influenza virus.