Synthesis and Anticancer Activity of Isoquinoline‐Imidazo[1,2‐a]Pyridine Linked Sulfonyl Derivatives

Abstract Several novel imidazo[1,2‐ a ]pyridine‐isoquinoline‐linked sulfonyl derivatives were designed and synthesized in this study. These derivatives were subsequently assessed in vitro for their inhibitory effects on EGFR kinases and their antiproliferative activity against two breast cancer cell lines. Several of the compounds demonstrated satisfactory efficacy in comparison to the primary agent, erlotinib. The most promising compounds, 6‐methoxy‐2‐methyl‐1‐(2‐phenyl‐6‐(1‐((3‐(trifluoromethyl)phenyl)sulfonyl)‐1,2,3,6‐tetrahydro pyridin‐4‐yl)imidazo[1,2‐a]pyridin‐3‐yl)‐1,2,3,4‐tetrahydro isoquinoline, 6‐methoxy‐2‐methyl‐1‐(2‐phenyl‐6‐(1‐((4‐(trifluoromethoxy) phenyl) sulfonyl)‐1,2,3,6‐tetrahydropyridin‐4‐yl)imidazo[1,2‐a]pyridin‐3‐yl)‐1,2,3,4‐tetrahydroisoquinoline, and 6‐methoxy‐2‐methyl‐1‐(2‐phenyl‐6‐(1‐((3‐(trifluoromethoxy)phenyl)sulfonyl)‐1,2,3,6‐tetrahydropyridin‐4‐yl) imidazo[1,2‐a]pyridin‐3‐yl)‐1,2,3,4‐tetrahydroisoquinoline, exhibited exceptional anticancer efficacy against MCF‐7 and MDA‐MB‐231 cancer cell lines, with IC 50 values ranging from 2.69 ± 0.24 to 7.64 ± 0.15 µM. Subsequently in vitro EGFR results demonstrated that the above potent compounds were more efficacious than the conventional medicine erlotinib. The molecular interactions of more potent compounds with the human epidermal growth factor receptor (EGFR) (PDB: 4HJO), which included a co‐crystallized ligand (erlotinib) were evaluated through in silico docking studies. It was noted that the binding energies of all evaluated compounds were higher than those of the standard drug, erlotinib.