Discovery of novel 1,2,4-triazole schiff bases hybridized with 1,4-naphthoquinones as potent STAT3 inhibitors.

Signal transducer and activator of transcription 3 (STAT3) is closely related to a variety of cancers. The research of novel STAT3 inhibitors is an important and meaningful project for pharmaceutical chemist. In this study, 10 novel 1,4-naphthoquinones carrying 1,2,4-triazole derivatives were synthesized via a four-step synthesis starting from 2-hydroxynaphthalene-1,4-dione. The inhibitory activities of these compounds against four cancer cells were tested at concentrations of 10, 1, 0.1 μM. The results exhibited that compound S1 showed outstanding anti-tumor activity. In addition, we tested the inhibitory curves of compound S1 on four types of cells, containing HeLa, HepG2, U87, LN229, with the IC50 values of 5.066 μM, 0.8089 μM, 1.970 μM, and 1.412 μM, respectively. Moreover, we verified the mechanism of S1 targeted to STAT3 through Western blot and qPCR experiments. Based on the good anti-tumor activity of S1 in cell level, we also tested the blood-brain barrier (BBB) crossing rate and the preliminary pharmacokinetic properties, and the result demonstrated S1 can cross the BBB. The above research indicated that compound S1 has excellent anti-tumor activity, which is worth for further study.