Design, Synthesis and Biological Evaluation of Novel 1,3,5-Triazines: Effect of Aromatic Ring Decoration on Affinity to 5-HT7 Receptor

Considering the key functions of the 5-HT7 receptor, especially in psychiatry, and the fact that effective and selective 5-HT7 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-HT7 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 mu M. Compound 12 exhibited less cardiotoxic effect than 2 on Danio rerio in vivo model.

Automated summary

In this study, novel 1,3,5-triazine derivatives were designed and synthesized as 5-HT7 receptor ligands. Two of the tested compounds showed high affinity and moderate metabolic stability, with low hepatotoxicity.