Building on our previous work on the synthesis of a series of 4H-chromene derivatives, we report herein for the first time the in vivo and in silico studies of ten chromene derivatives 5a-j as potential anti-metastatic cancer agents targeting through c-Jun N-terminal kinase (JNK). Compounds 5a-j were resynthesized using the protocol previously reported by our research group. Out of these, 5c, 5f-h and 5j showed good anti-metastatic cancer activity in Drosophila in vivo model, with 5f being the most active. It exhibited 27% rescue in metastatic cancer induced pupal lethality, whereas the standard drug sorafenib showed no rescue. Furthermore, 5f has significantly downregulated JNK and the metastasis promoting marker enzyme, matrix metalloproteinase-1 (MMP1) expression in Scribble (Scrib) knockdown induced Drosophila cancer tissues. In silico studies of all the compounds, 5a-j, demonstrated strong binding affinity with Drosophila JNK protein (PDB ID: 5AWM). Additionally, comparison of the docking positions of 5f in the 5AWM and human JNKs (PDB IDs: 1UKH and 3E7O) binding sites revealed a high degree of homology between them with respect to the similar set of amino acids interacting with the ligand. Compounds 5a-j also exhibited favourable pharmacokinetic properties with drug-like characteristics, as predicted by SwissADME analysis. The crystal structure of 5f was determined for the first time using single-crystal X-ray diffraction (SC-XRD) analysis. It crystallizes in a monoclinic crystal system with the space group P21/c, providing valuable insights into its structural features and molecular arrangement. The present findings strongly suggest that the chromene derivatives, represented by compound 5f, hold promise as potential anticancer agents targeting the metastatic stage in various epithelial cell-derived cancers.
