Alkyl derivatives of 7'-((3-mercapto-4-methyl-1,2,4-triazol-5-yl)methyl)-3-methylxanthine: synthesis and properties

Abstract

The pharmacophore centers of a molecule play a key role in understanding the interaction of drugs with their targets in the body and in the creation of new biologically active compounds. They enable the development of drugs with specific pharmacological properties, high selectivity and safety. Fragments of xanthine or 1,2,4-triazole in the structure of the substance contribute to the formation of pharmacophore centers and biological activity. The aim of the study was to synthesize S-alkyl derivatives of 7-((3-mercapto-4-methyl-1,2,4-triazol-5-yl)methyl)-3-methylxanthine and to determine the pharmacokinetic profile by in silico methods. The starting 3-methylxanthine was converted to 7-((3-mercapto-4-methyl-1,2,4-triazol-5-yl)methyl)-3-methylxanthine. The resulting thiol was subjected to S-alkylation with halogenalkanes. The structure and identity of the synthesized compounds were confirmed by elemental analysis, 1H NMR spectroscopy and chromatography-mass spectrometry. The pharmacokinetic parameters of the compounds and their compliance with the drug-like criteria were evaluated using the SwissADME on-line platform. The synthesized substances showed in the in silico studies were mostly able to overcome such drug-like filters as Lipinski, Gose, Weber, Egan, and Mugge, which predictively predetermines the positive pharmacokinetic profile of the studied compounds. The obtained values of such descriptors as molecular refraction and total area of polar surfaces of molecules, as well as lipophilicity indicators, only reinforce the above opinion. 10 S-alkyl derivatives of 7-((3-mercapto-4-methyl-1,2,4-triazol-5-yl)methyl)-3-methylxanthine were synthesized by the structural transformation of 3-methylxanthine with the intermediate formation of 1,2,4-triazole fragment with a SH-group at position 3, after which alkyl substituents were introduced. Predictive evaluation of the pharmacokinetic component of the drug-like parameters was performed, which allowed to substantiate the feasibility of further study of compounds to create a promising biologically active substance.