Synthesis and properties of 7-((6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)theophyllines

Abstract

The creation of new biologically active compounds is a promising area of modern medicinal chemistry. Heterocyclic systems play an important role in this process.Among them, it is necessary to note 1,2,4-triazole and xanthine, the presence of which in the structure of known medicines determines their pharmacological activity. The combination of these heterocycles within a single molecule can lead to the enhancement of the existing biological effect or the emergence of new useful properties.
 The aim of the work has been to synthesize new theophylline-containing 4-amino-1,2,4-triazole-3-thiol derivatives, study their physicochemical properties and predictive study of their biological potential.
 The research objects have been the 7-((6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]-thiadiazol-3-yl)methyl)theophylline, which were obtained by condensation of the starting 7-((4-amino-5-mercapto-1,2,4-triazol-3-yl)methyl)theophylline with aromatic carboxylic acids (benzoic,2-methoxybenzoic, 3-methoxybenzoic, 2-bromo-5-methoxybenzoic,2-bromo-4-fluorobenzoic, 2-chloro-4-nitrobenzoic, 2-bromo-5-nitrobenzoic) in phosphorus oxychloride medium under heating. The structure of the intermediate 7-((4-amino-5-mercapto-1,2,4-triazol-3-yl)methyl)theophylline was formed by a multistep chemical transformation of 1,3-dimethylxanthine. The structure of the synthesized compounds has been confirmed by elemental analysis, 1H NMR and IR spectroscopy, their individuality has been established by chromatography-mass spectrometry.
 The feasibility of further biological research has been preliminarily assessed by an in silico method, in particular, molecular docking. Cyclooxygenase-2, lanosterol 14α-demethylase and anaplastic lymphoma kinase have been used as model enzymes. The most likely activity, which is quite probable in a number of synthesized compounds, is antifungal. In this context, 7-((6-(2-bromo-5-methoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)methyl)theophylline looks particularly promising, as it exceeds ketoconazole in terms of the energy of intermolecular interactions with lanosterol 14α-demethylase.