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

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

doi:10.3390/molecules27227940

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

Molecules. 2022 Nov 16;27(22):7940. doi: 10.3390/molecules27227940.

Authors

Andrey V Khramchikhin¹, Mariya A Skryl'nikova^{1

2}, Iana L Esaulkova³, Ekaterina O Sinegubova³, Vladimir V Zarubaev³, Maxim A Gureev⁴, Aleksandra M Puzyk⁵, Vladimir A Ostrovskii^{2

6}

Affiliations

¹ Department of Organic Chemistry, Saint Petersburg State Institute of Technology, Technical University, 26 Moskovsky Avenue, 190013 St. Petersburg, Russia.
² Department of Chemistry and Technology of Organic Nitrogen Compounds, Saint Petersburg State Institute of Technology, Technical University, 26 Moskovsky Avenue, 190013 St. Petersburg, Russia.
³ Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology, 14 Mira Street, 197101 St. Petersburg, Russia.
⁴ Center of Bio and Cheminformatics, I. M. Sechenov First Moscow State Medical University, Trubetskaya 8/2, 119991 Moscow, Russia.
⁵ Research Park, Saint Petersburg State University, 26, Universitetskii Prospect, Petergof, 198504 St. Petersburg, Russia.
⁶ Saint Petersburg Federal Research Center of the Russian Academy of Sciences (SPC RAS), 39, 14th Line, 199178 St. Petersburg, Russia.

Abstract

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.

Keywords: [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines; [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines; annelated heterocycles; anti-viral activity; drug design; influenza virus.

MeSH terms

Antiviral Agents / pharmacology
Influenza A Virus, H1N1 Subtype*
Ligands
Thiadiazines* / pharmacology
Triazoles / pharmacology

Substances

Thiadiazines
Antiviral Agents
Triazoles
Ligands

Grants and funding

This research was funded by the Russian Foundation for Basic Research and the Committee on Science of the Republic of Armenia within the framework of the scientific project No. 20-53-05010 Arm_a/20RF-138; by the grant program for young scientists FASIE (2022–2023) No. 17837GU/2022.