Synthesis of Novel Anticancer Coumarin-Triazole-Chalcone Hybrids as Potential AKT Inhibitor

Abstract

This research article presents the synthesis of a novel series of hybrid analogues of Coumarin-Triazole-Chalcone, which are potential bioactives with a novel mode of action for anticancer therapy. The compounds were synthesized via aldol condensation and 1,3-dipolar cycloaddition, resulting in the generation of hybrid heterocyclic systems that combine two or more pharmacophores. The synthesized compounds were then screened for anticancer activity against various human cancer cell lines, including A549 (lung cancer), HeLa (Cervix carcinoma), PANC1 (pancreatic cancer), HT1080 (Fibrosarcoma) and HEK293 (Human embryonic kidney cells), in in vitro mode. One of the compounds, para-nitrile chalcone 9a, demonstrated significant IC₅₀ values in the range of 3.1 to 7.02 µg/ml when compared to the others. All the compounds 9a-9d have shown higher IC₅₀ values towards HEK-293 cells indicating their non-toxic nature towards normal cells. Furthermore, in silico approaches were employed to assess the efficacy of compounds that were active in the MTT assay against molecular targets. The authors conducted docking studies of the proteins PI3K and AKT, which are common target biomarkers in Pancreatic cancer, Lung cancer, Cervical cancer, and Fibrosarcoma, with compound 9a and some known inhibitors. The results showed that compound 9a had a good binding affinity with AKT (-10.6) and PI3K (-10.3). However, it was found to be more specific for AKT as its binding site amino acid interactions were similar to those of known AKT inhibitors. These findings provide evidence that hybrid heterocyclic systems may be useful for developing potential bioactives with a novel mode of action for anticancer therapy.