Design of novel quinazoline-chalcone hybrids as potent epidermal growth factor receptor inhibitors

Abstract

This study successfully designed and synthesized a novel series of quinazoline-chalcone hybrids. The key innovation lies in the molecular hybridization of the pharmacophoric quinazoline scaffold with a chalcone moiety, creating new chemical entities to exploit potential synergistic antitumor effects. A concise multi-step synthetic route was efficiently implemented. Preliminary evaluation demonstrated that a majority of these hybrids exhibited potent antiproliferative activity against non-small cell lung cancer (NSCLC) cell lines (A549 and H1975) in vitro. Molecular docking studies suggested against epidermal growth factor receptor (EGFR) inhibition as a potential mechanism, with the compounds forming stable interactions with the kinase domain. Furthermore, in silico absorption, distribution, metabolism, and excretion (ADME) and toxicity predictions by SwissADME and ProTox 3.0, respectively, indicated promising drug-like properties and safety profiles. However, the cytotoxicity was assessed only on cancer cell lines, and the selectivity against normal cells remains to be determined. Despite this limitation, the compelling initial results position these novel hybrids as promising leads for future optimization and development.