Development of Novel [1,2,4]-triazine-3-thioether hybrids Bearing Bioactive Scaffolds with Multitarget Potential

The class of nitrogen-containing heterocycles known as [1,2,4]-triazines is present in molecules that exhibit diverse biological activities, such as antitumor, antibacterial, anti-inflammatory, antiviral,¹ and anticonvulsant² properties. The hybridization of this scaffold with other cycles that also display multiple pharmacological activities has become a target for novel studies. Furthermore, 1,4-benzoquinones and indoles are present in several active compounds and are widely investigated as multi-target agents. Investigated the effect of fusing the [1,2,4]-triazine heterocycle with 1,4-naphthoquinones and indoles, scarcely explored naphtho-[1,2,4]-triazines³ and indole-[1,2,4]-triazines were synthesized.

In this work, the synthesis was initiated using the dicarbonyl compounds lawsone, lapachol, iso-lapachol, and isatin in a cycloaddition reaction with thiosemicarbazide under reflux in water, yielding the respective naphtho-[1,2,4]-triazine-3-thioethers and indole-[1,2,4]-triazine-3-thioethers in yields ranging from 15% to 97%. Subsequent chemoselective alkylation afforded the corresponding thioalkylated compounds in yields between 13% and 49%. These compounds will be evaluated against multiple medicinal chemistry multitargets.