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.