Synthesis and biological evaluation of novel [1,2,3]triazolo-pyrrolo[1,2-a]pyrido[4,3-d]pyrimidines as EGFR targeting anticancer agents.

• One-pot synthesis of fused [ 1 , 2 , 3 ]triazolo-pyrrolo[1,2- a ]pyrido[4,3- d ]pyrimidines (5a-5n) via CuAAC followed by C C bond coupling. • The fused 1,2,3-triazoles exhibited anti-cancer activity and epidermal growth factor receptor (EGFR) was carried out for potent compounds. • In silico ADME and molecular docking studies were also held potent compounds for the future anticancer drug discovery initiatives. • Theoretical investigation of compound 5n utilized DFT/B3LYP basis set and characterized their physical properties. Herein, we synthesized some new fused [1,2,3]triazolo-pyrrolo[1,2-a]pyrido[4,3-d]pyrimidines via click chemistry followed by carbon-carbon bond coupling as key approach and then characterized their structures by IR, NMR, mass and CHN analysis techniques. The structural parameters of compound 5n were also derived from geometry optimization. Molecular electrostatic potential (MEP), HOMO–LUMO energy gap, and Mulliken atomic charges were calculated. Later, the anticancer activity of the synthesized compounds was screened in vitro against different human cancer cell lines like MCF-7, NCI-H460, and A-549 and the results were compared with standard drug erlotinib. Most of the investigated compounds like 5c, 5e, 5f, 5j, 5 m and 5n were found to be active against MCF-7. Specifically, compounds 5c and 5n had superior activity against MCF-7 and remarkable activity against A-549. The results of the inhibitory assay of most active compounds 5c and 5n against the wild type tyrosine kinase EGFR (PBS Bioscience, catalog # 40321), which is one of the enzymes expressed in the MCF-7 and A-549 cell lines revealed that both compounds had greater potency in inhibiting tyrosine kinase EGFR than the standard drug erlotinib. The in silico studies of six active compounds 5c, 5e, 5f, 5j, 5 m, 5n and erlotinib were also carried out on EGFR receptor and observed that all the six compounds had appreciable binding energies and inhibition constants than the standard drug erlotinib. Finally, the in silico pharmacokinetic profile was predicted for potent compounds 5c, 5e, 5f, 5j, 5 m and 5n using SWISS/ADME and pkCSM, where, all the compounds followed Lipinski, Lipinski, Veber, Egan and Muegge rules without any deviation. [Display omitted] [ABSTRACT FROM AUTHOR]