Molecular docking, synthesis and pharmacological screening of indole-3-mannich bases as egfr kinase inhibitors to combat non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) has been identified as a clinically relevant target for the treatment of advanced non-small-cell lung cancer patients (NSCLC). EGFR-directed tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in patients with advanced NSCLC. The drugs Erlotinib and Osimertinib are commonly prescribed for the NSCLC treatment so docking studies were carried out on the two X-ray crystallographic Protein Data Bank (PDB) IDs, 6LUD and 1M17, with co-crystallized molecules Osimertinib and Erlotinib, respectively. Similar to indole scaffold present in Osimertinib, the series was designed with substitutions at third position on indole with different aldehydes and secondary amines to form mannich bases. On docking of the designed series in both active sites, IM_23, IM_24, IM_25, IM_44, IM_45, IM_50, IM_52, IM_57, and IM_63 demonstrated interactions with active site residues in both the pdb structures. In silico ADME studies were performed to judge the drug likeliness. The analogs with favourable computational results were synthesized utilizing green, benign method and characterized. The synthesized analogs were assessed for anti-proliferative properties on the human lung cancer A549 cell line in vitro. IM_23 and IM_45 exhibited prominent activity. Correlation of docking and screening results indicated that electron-donating substituents on phenyl ring of the analogues showcased more interactions with crucial residues in active site such as Met 793 with better activity profile than electron-donating groups. In conclusion, some analogues exhibit potential as EGFR inhibitors to target non-small cell lung cancer. Further, the findings may offer perceptions into the possible EGFR binding properties, which may aid in the optimization and further development of more promising analogs.