Synthesis, Molecular Docking, In-Vitro Anticancer Activity Screening, and Structure-Activity Relationship Studies of Novel Quinazoline Derivatives as Potential EGFR Tyrosine Kinase Inhibitors for Targeted Cancer Therapy

Ishaan Malhotra, Kavya Srinivas, Dr. Reyansh Mehta

Department of Cancer Pharmacology and Translational Therapeutics, Basavatarakam Indo American Cancer Hospital & Research Institute, Hyderabad

1. Abstract

Cancer continues to be a major cause of death globally, driving the ongoing creation of targeted treatments that offer better selectivity and less systemic toxicity. The epidermal growth factor receptor (EGFR) tyrosine kinase has been identified as a key molecular target for various cancers, such as non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer. Quinazoline derivatives are a significant scaffold in medicinal chemistry and are commonly used in approved EGFR inhibitors like gefitinib, erlotinib, and afatinib. This research article provides an in-depth examination of the rational design, synthesis, molecular docking analysis, in-vitro anticancer evaluation, and structure-activity relationship (SAR) studies of new quinazoline derivatives as potential EGFR tyrosine kinase inhibitors. The proposed derivatives were crafted based on the pharmacophoric needs of EGFR ATP-binding pocket interactions. The synthetic approach involved multi-step condensation and cyclization reactions starting from substituted anthranilic acids to produce 4-anilinoquinazoline analogues with various electron-donating and electron-withdrawing groups. The synthesized compounds were characterized using FT-IR, ¹H NMR, ¹³C NMR, and mass spectrometry. Molecular docking studies were conducted with AutoDock Vina and validated against EGFR crystal structures to assess binding affinity, hydrogen bonding interactions, and hydrophobic contacts. Biological evaluation included in-vitro cytotoxicity screening against selected human cancer cell lines (MCF-7, A549, HepG2) using the MTT assay, followed by apoptosis and cell-cycle analysis for potent compounds. Several derivatives showed notable antiproliferative activity with IC₅₀ values ranging from low micromolar to nanomolar, similar to standard EGFR inhibitors. Docking results indicated stable binding interactions with crucial amino acid residues such as Met769, Lys721, and Asp831 in the EGFR active site, confirming their inhibitory potential. SAR analysis indicated that substitution at the 4-anilino position and the presence of heterocyclic moieties improved activity and binding affinity. In summary, the study illustrates that rationally designed quinazoline derivatives can act as promising EGFR tyrosine kinase inhibitors with strong anticancer activity. The combination of synthetic chemistry, computational modeling, and biological assays offers a solid foundation for future optimization and development of targeted anticancer treatments.

2. Keywords

Derivatives of quinazoline; inhibitors of EGFR tyrosine kinase; molecular docking studies; anticancer properties; relationship between structure and activity; cancer therapy targeting specific pathways; heterocyclic chemical compounds; inhibition of kinase activity.