Synthesis of Heterocycle-Appended 4-Aminoquinazolines with Antiproliferative Properties and Potential to Inhibit Tyrosine Kinases

Abstract

The 4-anilinoquinazoline derivatives have established themselves as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation. Molecular hybridization to replace the aniline moiety with a heterocyclic scaffold has been found to lead to heterocycle-appended quinazolines with enhanced biological properties and reduced side effects. We have also merged 7-amino-2-arylindole and 7-amino-2-arylbenzofuran moieties with the 2-aryl-4-chloroquinazolines to afford indole- and benzofuran-appended 4-aminoquinazoline analogues of gefitinib. The prepared molecular hybrids were evaluated for antigrowth effect against a panel of EGFR-positive cell lines, such as the human lung cancer (A549), epithelial colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A), breast adenocarcinoma (MCF-7) and cervical cancer (HeLa) cell lines. These compounds were also evaluated for their ability to inhibit EGFR tyrosine kinase phosphorylation complemented with molecular docking into the adenosine triphosphate (ATP) binding site.