Novel [1,2,4]triazolo[3,4-<i>b</i>][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-<i>b</i>][1,3,4]thiadiazepine Derivatives: Synthesis, Anti-Viral In Vitro Study and Target Validation Activity
Andrey V. Khramchikhin,
Mariya A. Skryl’nikova,
Iana L. Esaulkova,
Ekaterina O. Sinegubova,
Vladimir V. Zarubaev,
Maxim A. Gureev,
Aleksandra M. Puzyk,
Vladimir A. Ostrovskii
Affiliations
Andrey V. Khramchikhin
Department of Organic Chemistry, Saint Petersburg State Institute of Technology, Technical University, 26 Moskovsky Avenue, 190013 St. Petersburg, Russia
Mariya A. Skryl’nikova
Department of Organic Chemistry, Saint Petersburg State Institute of Technology, Technical University, 26 Moskovsky Avenue, 190013 St. Petersburg, Russia
Iana L. Esaulkova
Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 St. Petersburg, Russia
Ekaterina O. Sinegubova
Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 St. Petersburg, Russia
Vladimir V. Zarubaev
Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 St. Petersburg, Russia
Maxim A. Gureev
Center of Bio and Cheminformatics, I. M. Sechenov First Moscow State Medical University, Trubetskaya 8/2, 119991 Moscow, Russia
Aleksandra M. Puzyk
Research Park, Saint Petersburg State University, 26, Universitetskii Prospect, Petergof, 198504 St. Petersburg, Russia
Vladimir A. Ostrovskii
Department of Chemistry and Technology of Organic Nitrogen Compounds, Saint Petersburg State Institute of Technology, Technical University, 26 Moskovsky Avenue, 190013 St. Petersburg, Russia
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.
