Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB

Samy Mohamady, The British University in Egypt
Abdullah Ahmed Gibriel, The British University in Egypt
Mahmoud Salama Ahmed, UT Southwestern Medical School
Moataz S. Hendy, The British University in Egypt
Bassem H. Naguib, The British University in Egypt


© 2020 Elsevier Inc. A novel synthetic approach was developed for the synthesis of 3-hydrazinotriazolothiadiazines in just one step from Purpald and phenacyl bromides. They were then selectively tethered to naphthoquinone fragments through hydrazine moiety generating novel Naphthoquinone-hydrazinotriazolothiadiazine analogues. In vitro cytotoxicity for the synthesized chemical entities was validated against HepG2 and MCF-7 cell lines and recorded IC50 inhibitory profile range of 0.07–19.68 µM and 1.19–67.32 µM respectively. Among the synthesized series, compound 4c had maximal cytotoxicity against HepG2 and was therefore selected for further downstream biological investigations. Caspase 3 apoptotic marker was significantly upregulated in cells treated with compound 4c with induction of apoptosis at Pre-G1 phase and cell death at G2/M phase. Compounds 4a, 4c and 4d exhibited the most powerful inhibitory range (0.55–0.64 µM) against Topo IIB. Molecular docking study revealed potential interactions of those compounds within the ATP catalytic binding domain of Topo-IIB with high scores. In conclusion, the novel Naphthoquinone-hydrazinotriazolothiadiazine analogues could serve as promising anticancer agents through inhibition of Topoisomerase–IIB.