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

Abstract

As part of our ongoing efforts to produce promising cytotoxic agents, the novel compounds, 5-(4-(diethylamino)-2-((1-substitutedphenyl-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1,3,4-thiadiazol-2yl)pyrrolidine-2,5-dione derivatives (9a-l) were developed, synthesised, 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 synthsized were evaluated for their anticancer activity against human oesophageal carcinoma cell line KYSE-450 and human pancreatic carcinoma cell line MIA PaCa-2 cells. The compounds 9b, 9i, 9j, and 9l exhibited potential cytotoxic activity against KYSE-450 and MIAPaCa-2 cells, according to cytotoxic evaluation data. Compound 9j had greater anti-cancer potential relative to 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 signi cantly more effective against both ARK-1 and ERK-2 enzymes, indicating its dual inhibition potential. Docking analysis culminated that 9k, 9j, and 9i have substantial docking scores with the ARK-1 receptor, indicating the presence of strong binding a nities. Signi cant binding interactions between molecules 9j and 9h and the ERK-2 receptor suggest an inhibitory effect. Hence the compounds are promising dual inhibitors of ARK-A/ERK2.