Synthesis and biological activity of fluorinated 7-aryl-2-pyridyl-6,7-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-amines

In our lead finding program, 12 new fluorinated 7-aryl-2-pyridyl-6,7-dihydro1,2,4]triazolo1,5-a]1,3,5]triazin-5-amines were prepared via a practical three-step procedure starting from (iso)nicotinic hydrazides. The fluorine substituted aryl fragment was introduced in the last step through cyclocondensation of N-(3-pyridyl-1,2,4-triazol-5-yl)guanidines and fluoro/trifluoromethyl substituted benzaldehydes. The structures of the compounds were confirmed by ¹H and ¹³C NMR spectral data. The tautomeric preferences for the compounds were established using 2D NOESY experiments. The antiproliferative activity of the synthesized 1,2,4-triazolo1,5-a]1,3,5]triazines was evaluated against breast, colon and lung cancer cell lines. The highest antiproliferative activity in the series was found for 2-(pyridine-3-yl)-7-(4-trifluoromethylphenyl)-6,7-dihydro1,2,4]triazolo1,5-a]1,3,5]triazin-5-amine. The lack of inhibitory activity against bovine dihydrofolate reductase (DHFR) indicated that the antiproliferative activity was realized via other mechanisms.