Imidazo[1,2,4]triazolone and fused imidazo[1,2,4]triazolone derivatives: Synthesis, in vitro anticancer screening, CDK2 inhibitory activity, and molecular modeling studies

In continuation of our program for synthesizing novel imidazotriazole scaffolds, we report herein the synthesis of new fifteen substituted and fused imidazotriazole derivatives via different addition and cyclocondensation pathways. Thirteen compounds have been tested for their antiproliferative activity against 60 NCI cell lines. Compounds 3, 15 and 17 were the most active among the synthesized series. Imidazo[2,1‐c][1,2,4]triazolone derivative 3 showed high activity against leukemia K‐562 (51.00%), RPMI‐8226 (68.36%) and breast cancer MCF‐7 (56.76%) cell lines. While compound 15 exhibited high potency against colon cancer HCT‐15 (59.33%), CNS cancer SNB‐75 (57.06%) and renal cancer UO‐31 (50.5%) cell lines. Bis[1,2,4]triazolopurin‐7‐one derivative 17 showed strong activity against CNS cancer SNB‐75 cell line (54.32%). Compounds 3, 15 and 17 were evaluated through molecular modeling and docking techniques to give us a closer look on their binding mode with CDK2. The in vitro inhibitory activity against CDK2 was also performed for compounds 3 and 17. Compound 3 was subjected to further investigations by studying its effect on cell cycle progression and cell apoptosis in MCF‐7 cell line. It caused apoptosis, necrosis and induced cell cycle arrest at G2/M phase in MCF‐7 cell. Hydrazinyl side chain cyclization with chalcone.