Synthesis of Imidazo[1,2‐a]pyridine‐Isoquinoline Derivatives as Potent EGFR Inhibiting Anticancer Agents

Abstract

Herein, we synthesized some new imidazo[1,2‐a]pyridine‐isoquinoline hybrids (8 a–8 x) and investigated their anticancer activity on two human breast cancer cell lines, namely MCF‐7 and MDA‐MB231. Generally, most of them displayed higher activity on both breast cell lines than the reference drug. Specifically, compounds (2,6‐difluorophenyl)(6‐methoxy‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐3,4‐dihydroisoquinolin‐2(1H)‐yl)methanone, (6‐methoxy‐1‐(2‐phenyl imidazo[1,2‐a]pyridin‐3‐yl)‐3,4‐dihydroisoquinolin‐2(1H)‐yl)(6‐methoxy pyridin‐3‐yl)methanone, (6‐methoxy‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐3,4‐dihydroisoquinolin‐2(1H)‐yl)(pyrimidin‐5‐yl) methanone, 6‐methoxy‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐2‐(phenylsulfonyl)‐1,2,3,4‐tetrahydro isoquinoline, 6‐methoxy‐1‐(2‐phenyl imidazo[1,2‐a]pyridin‐3‐yl)‐2‐tosyl‐1,2,3,4‐tetrahydroisoquinoline, and 6‐methoxy‐2‐((4‐methoxyphenyl)sulfonyl)‐1‐(2‐phenylimidazo[1,2‐a] pyridin‐3‐yl)‐1,2,3,4‐tetrahydroisoquinoline showed higher activity against tested cancer cell lines as compared to the erlotinib. The ability of potent compounds to inhibit the tyrosine kinase EGFR was then studied and found that compounds (6‐methoxy‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐3,4‐dihydroisoquinolin‐2(1H)‐yl)(pyrimidin‐5‐yl) methanone, 6‐methoxy‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐2‐tosyl‐1,2,3,4‐tetra hydroisoquinoline, and 6‐methoxy‐2‐((4‐methoxyphenyl) sulfonyl)‐1‐(2‐phenylimidazo[1,2‐a]pyridin‐3‐yl)‐1,2,3,4‐tetrahydro isoquinoline exhibited promising potency in comparison to the erlotinib. In silico investigations of the most effective compounds were also performed to find interactions with the EGFR receptor that robustly bind to the protein, and energy estimates were in good agreement with the corresponding IC50 values.