Synthesis, crystal structure determination and antiproliferative activity of novel 2-amino-4-aryl-4,10-dihydro[1,3,5]triazino[1,2-a]benzimidazoles

This manuscript describes the synthesis of novel 2-amino-4-aryl-4,10-dihydro-[1,3,5]triazino[1,2-a]benzimidazoles as hydrochloride salts 4a-n and 5b which were prepared in the reaction of cyclocondensation between 2-guanidinobenzimidazole and versatile heteroaromatic aldehydes. Structures of all prepared compounds have been studied by using 1H and 13C NMR, IR and UV/Vis spectroscopy.The crystal and molecular structure of 4f was determined by X-ray diffraction on single crystals. The molecule of 2-amino-4-(4′-methylphenyl)-4,10-dihydro[1,3,5]triazino[1,2-a]benzimidazole hydrochloride 4f (C16H16N5+·Cl−) exists in the solid state in one of the possible tautomeric forms, being protonated at the one of the nitrogen atoms of the 1,4-dihydrotriazine ring. The molecule is highly delocalized within the 4,10-dihydro[1,3,5]triazino[1,2-a]benzimidazole moiety with the highest deviation from the plane for the methine carbon atom and the protonated nitrogen atom of the 1,4-dihydrotriazine ring. The cations are joined via   N–H⋯N hydrogen bonds into R22(8) centrosymmetric dimers. Cation dimers are further connected with Cl− ions via N–H⋯Cl and C–H⋯Cl hydrogen bonds into 2D chains spreading along the b axis. The obtained single-crystal X-ray structure determination unequivocally confirms tautomeric form of the compound present in the solid-state and can represent tantative pattern for other prepared compounds.All prepared compounds were tested on their antiproliferative activity in vitro on several human cancer cell lines. Compound 4m was the most active one (IC50 ≈ 20 μM), while compounds 4d, 4f, 4k, 4l4m showed moderate, but non-selective, antiproliferative activity with IC50 25–60 μM.

► Synthesis of 2-amino-4-aryl-4,10-dihydro-[1,3,5]triazino[1,2-a]benzimidazole hydrochlorides. ► X-ray diffraction on single crystals. ► Spectroscopic characterization by NMR, UV and IR spectroscopy. ► Antiproliferative activity in vitro.