Synthesis, in-silico based virtual screening,anti-cancer potential of novel1,2,3-triazole-thiadiazole hybrid derivatives as Aurora kinase A (ARK-A) and Extracellular regulated kinase 2 (ERK2) dual inhibitors

As part of our ongoing efforts to produce promising cytotoxic agents, the novel compounds, 5-(4-(diethylamino)-2-((1-substitutedphenyl-1 H -1,2,3-triazol-4-yl)methoxy)phenyl)-1,3,4-thiadiazol-2-yl)pyrrolidine-2,5-dione derivatives ( 9a-l ) were developed, synthesized, and characterized using several analytical techniques, including 1 H NMR, 13 C NMR, and LC-MS. New series of 1,2,3-triazole and thiadiazole molecular hybrids synthesized were evaluated for their anti-cancer activity against human esophageal carcinoma cell line KYSE-450 and human pancreatic carcinoma cell line MIA PaCa-2 cells. According to cytotoxic evaluation data, compounds 9b , 9i , 9j , and 9l exhibited potential cytotoxic activity against KYSE-450 and MIAPaCa-2 cells. Compound 9j had more significant anti-cancer potential than the standard employed across all compounds evaluated. The remaining compounds exhibited moderate to weak anti-proliferative potential. In-vitro kinase inhibition of compound 9j was significantly more effective against ARK-A and ERK2 enzymes, indicating its dual inhibition potential. Docking analysis showed that 9k, 9j , and 9i have substantial docking scores with the ARK-A receptor, indicating the presence of strong binding affinities. Significant binding interactions between molecules 9j and 9h and the ERK2 receptor suggest an inhibitory effect. Hence the compounds are promising dual inhibitors of ARK-A/ERK2. Graphical Abstract