Design, Synthesis, and Biological Evaluation of Novel 7-[1,2,4]Triazolo[3,4-][1,3,4]thiadiazine Inhibitors as Antitumor Agents.

A series of novel anticancer hydrazinotriazolothiadiazine-based derivatives were designed based on the structure-activity relationship of the previously reported anticancer triazolothiadiazines. These derivatives were synthesized and biologically screened against full NCI-60 cancer cell lines revealing compound with a potential antiproliferative effect. was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β) with IC equal to 0.883 μM and 14-fold selectivity over CDK2. Also, increased active caspase-3 levels, induced cell cycle arrest at the G2-M phase, and increased the percentage of Annexin V-fluorescein isothiocyanate-positive apoptotic cells in PC-3 prostate cancer-treated cells. Molecular docking and dynamics were performed to predict the binding mode of in the GSK-3β ATP binding site. can be utilized as a starting scaffold for developing potential GSK-3β inhibitors.