Novel 1,2,4-Triazole- and Tetrazole-Containing 4H-Thiopyrano[2,3-b]quinolines: Synthesis Based on the Thio-Michael/aza-Morita-Baylis-Hillman Tandem Reaction and Investigation of Antiviral Activity.

A novel method for synthesizing 1,2,4-triazole- and tetrazole-containing 4H-thiopyrano[2,3-b]quinolines using a new combination of the thio-Michael and aza-Morita-Baylis-Hillman reactions was developed. Target compounds were evaluated for their cytotoxicities and antiviral activities against influenza A/Puerto Rico/8/34 virus in MDCK cells. The compounds showed low toxicity and some exhibited moderate antiviral activity. Molecular docking identified the M2 channel and polymerase basic protein 2 as potential targets. We observed that the antiviral activity of thiopyrano[2,3-b]quinolines is notably affected by both the nature and position of the substituent within the tetrazole ring, as well as the substituent within the benzene moiety of quinoline. These findings contribute to the further search for new antiviral agents against influenza A viruses among derivatives of thiopyrano[2,3-b]quinoline.

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine Derivatives: Synthesis, Anti-Viral In Vitro Study and Target Validation Activity.

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level.

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.