Design, Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT(7) Receptor

Considering the key functions of the 5-HT(7) receptor, especially in psychiatry, and the fact that effective and selective 5-HT(7) receptor ligands are yet to be available, in this work, we designed and synthesized novel 1,3,5-triazine derivatives particularly based on the evaluation of the effect of substituents at aromatic rings on biological activity. The tested compounds showed high affinity to the 5-HT(7) receptor, particularly ligands N(2)-(2-(5-fluoro-1H-indol-3-yl)ethyl)-N(4)-phenethyl-1,3,5-triazine-2,4,6-triamine 2 (K(i) = 8 nM) and N(2)-(2-(1H-indol-3-yl)ethyl)-N(4)-(2-((4-fluorophenyl)amino)ethyl)-1,3,5-triazine-2,4,6-triamine 12 (K(i) = 18 nM) which showed moderate metabolic stability, and affinity to the CYP3A4 isoenzyme. As for the hepatotoxicity evaluation, the tested compounds showed moderate cytotoxicity only at concentrations above 50 µM. Compound 12 exhibited less cardiotoxic effect than 2 on Danio rerio in vivo model.