SYNTHESIS OF NEW HYBRID MOLECULES WITH 1,3,5-TRIAZINE AND HYDROQUINOLINE MOIETIES

Abstract

The article describes a method for the synthesis of hybrid molecules based on the 1,3,5-triazine platform and containing additional pharmacophore fragments of 2,2,4-trimethyl-1,2-dihydroquinoline, 4-aryl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline, indoline or piperidine. The obtained compounds are promising for studying their biological action. The described synthesis method includes the interaction of indolin-1-ylimidoguanidine and piperidine-1-ylimidoguanidine with carbon disulfide to form 4-amino-6-(indolin-1-yl)-1,3,5-triazine-2-thiol and 4-amino-6-(piperidin-1-yl)-1,3,5-triazine-2-thiol, respectively. 4-Amino-6-R-1,3,5-triazine-2-thiols have two nucleophilic centers: an amino and a mercapto group, so they can be introduced in subsequent reactions with electrophilic reagents such as alkyl halides. Alkylation of the latter with N-chloroacetyl derivatives of hydroquinolines gives hybrid heterocyclic matrices: 2-((4-amino-6-(indolin-1-yl)-1,3,5-triazin-2-yl)thio)-1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-ones, 2-((4-amino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)thio)-1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-ones, 2-((4-amino-6-(indolin-1-yl)-1,3,5-triazin-2-yl)thio)-1-(4-(4-aryl-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl)ethan-1-ones and 2-((4-amino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)thio)-1-(4-(4-aryl-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl)ethan-1-ones. The structure of the obtained compounds was characterized by high performance liquid chromatography with mass spectrometry, as well as by 1H and 13C NMR spectroscopy. For the compounds with the dihydroquinoline fragment in their structure, the singlet of the CH proton of the pyridine cycle of the hydroquinoline fragment, which is visible in the 5.56-5.61 ppm region, is characteristic. In turn, in the spectra of compounds with the tetrahydroquinoline fragment, there is a characteristic signal of the CH2 group of the hydropyridine cycle of the quinoline fragment in the form of two sets of multiplets at 0.99-1.09 and 1.61-1.71 ppm. The presence of several pharmacophore fragments in the molecules determines the high probability of their biological activity. The anticoagulant activity of 2-((4-amino-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)thio)-1-(2,2,4-trimethylquinolin-1(2H)-yl)ethan-1-ones due to their inhibitory effect on blood coagulation factors Xa is described. A series of new hybrid molecules on the platform of 1,3,5-triazine containing additionally linearly linked hydroquinoline and indoline (piperidine) cycles was obtained in the course of this research. Initial screening of anticoagulant activity was performed and moderate activity of 2-((4-amino-6-(piperidin-1-yl)-1,3,5-triazine-2-yl)thio)-1-(2,2,4-trimethylquinoline-1(2H)-yl)ethane-1-ones against coagulation factor Xa was shown.