Developing lipophilic aromatic halogenated fused systems with specific ring orientations, leading to potent anticancer analogs and targeting the c-Src Kinase enzyme

Abstract This work presents the combined microwave assisted synthesis, spectroscopic analyses, cytotoxic effects, and molecular docking studies of the chromene fused ring systems with various substituents of the terminal halogenated phenyl ring derivatives of 6-methoxy-4 H -benzo [ h ]chromene ( 4a-m ). The structures of the synthesized compounds were established on the basis of their spectral data, IR, 1 H NMR, 13 C NMR, 13 C NMR-DEPT, and MS data. The target compounds were evaluated for their antitumor activities against three cancer cell lines: MCF-7, HCT-116, and HepG-2, in comparison to Vinblastine and Colchicine as reference drugs with the usage of a MTT colorimetric assay. The most active compounds were subjected to further mechanistic analysis through the assay of the c-Src Kinase inhibition activity. The SAR studies reported that the substitution at the 4-position of the 2-amino-4 H -benzo [ h ]chromene nucleus with specific halogen atoms and lipophilic characters increased the ability of the molecule against the different cell lines. The Molecular Operating Environment (MOE) was used to evaluate the interactions between the ligand and the c-Src Kinase enzyme. Compound 4m , having the 3,5-dibromo-2-methoxyphenyl group attached to the 4 H -benzo [ h ]chromene moiety at the 4-postion, exhibited a promising interaction with the c-Src Kinase, which leads to a strong inhibition of this enzyme.