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

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.

Synthetic Methods and Pharmacological Potentials of Triazolothiadiazines: A Review

“…The reaction of 4-amino-5-substituted-4H-1,2,4-triazole-3-thiols 1 with hydrazonoyl chlorides 2 in refluxing ethanol or dioxane with Et 3 N afforded (7Z)-7- [2-(aryl)hydrazinyli dene]-6-methyl-7H- [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazines 3 [6,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The produced compounds underwent in vitro testing against 11 candida species and were compared to the conventional medication ketoconazole.…”

“…Oxidation of 35 in acetonitrile using MnO2 gave [1,2,4]triazolo [3,4-b][1,3,4]thiadiazines 36. However, hydrogenation 36 with sodium borohydride afforded 35 [11,31] (Scheme 12). Scheme 12.…”

“…Triazolothiadiazine derivatives have a wide range of therapeutic activities such as antimicrobial [ 2 , 3 ], tubulin inhibition [ 4 ], anticancer [ 5 , 6 , 7 , 8 ], anti-candida [ 9 ], and antiviral activity against highly pathogenic avian influenza (HPAI H 5 N 1 ) [ 10 ], antiviral [ 11 ], antiproliferative [ 12 ], aromatase inhibition [ 13 ], analgesic, anti-inflammatory, and antioxidant effects [ 14 , 15 ]. Figure 2 depicts the retrosynthetic analysis used to create the triazolothiadiazine derivatives, involving six main routes: I , II , III , IV , V , and VI .…”