Quinoline–hydrazone hybrids as dual mutant EGFR inhibitors with promising metallic nanoparticle loading: rationalized design, synthesis, biological investigation and computational studies

Abstract

Overexpression of epithelial growth factor receptor (EGFR) has been identified as the driving mechanism within the development and progression of several cancers. The emergence of resistance induced by mutations in the EGFR gene has presented a formidable challenge in the development of new EGFR inhibitors. Guided by the pharmacophoric features of EGFR inhibitors, a new series of quinoline–hydrazone hybrids (4–15) were rationally designed, synthesized, and pharmacologically evaluated against liver HepG-2 and breast MCF-7 cancerous as well as normal mammary gland epithelial cell lines. Compounds 13–15 showed low-to-sub micromolar inhibitory activities (IC₅₀ = 0.98 ± 0.03 to 7.37 ± 0.69 μM) for the studied cell lines, while compound 14 exhibited a safety profile against normal cells. Moreover, significant selectivity indices were also depicted for compound 14 against two mutant EGFRs (T790M and L858R) in relation to the wild-type form. Molecular aspects of compound–target binding were postulated through valid molecular modelling studies on both wild-type and mutant EGFRs. Additionally, the drug-likeness and clinical candidacy of the three top-active compounds were evaluated through comprehensive computational tools of pharmacokinetic/ADMET profiling and mutagenicity prediction. Embarking on improving the compound's pharmaceutical properties, three different metal-based nanoparticle formulations (silver, selenium, and cobalt tetraoxide) for compound 14 depicted enhanced cytotoxicity compared to the parent compound. These findings revealed compound 14 as a promising anticancer lead candidate with prospects for future optimization and development.