IMesCuCl/TBHP system for aqueous oxidative amidation: Synthesis of new amide derivatives as EGFR targeting anti-breast cancer agents and computational studies.

• A base free and efficient IMesCuCl/TBHP promoted oxidative amidation approach to get new 1,4-benzoxazinone-tetrazole-amides. • Compound 12g showed greater activity than the Erlotinib against MDA-MB-231 and MCF-7 cancer cell lines. • Compounds 12a and 12c showed greater activity than the Erlotinib against MCF-7. • Compound 12g showed comparable potency against tyrosine kinase EGFR with the Erlotinib. • Compounds 12a, 12c and 12g displayed better binding energies and inhibition constants on EGFR (PDB ID-4HJO) than the Erlotinib. • Most potent compound 12g was characterized by DFT studies. A base free and aqueous synthesis of some new 1,4-benzoxazinone-tetrazole containing amides via tert ‑butyl hydroperoxide (TBHP) mediated oxidative coupling of 2-(5-(2-(3-oxo-2,3-dihydro-4 H -benzo[ b ][1,4]oxazin-4-yl)ethyl)-2 H -tetrazol-2-yl)acetaldehyde (10) with anilines (11a-n) under (1,3-dimesityl-2,3-dihydro-1 H -imidazol-2-yl)copper(I) chloride (IMesCuCl) catalysis was reported herein for the first time. All these compounds (12a-n) were screened for their in vitro anti-breast cancer activity against two human breast cancer cell lines (MDA-MB-231 and MCF-7). Out of all, compound 12g showed greater activity than the Erlotinib on two cell lines with IC 50 values in the range of 4.12–7.03 μg/mL. As well, compounds 12a and 12c showed greater activity than the Erlotinib on MCF-7 with IC 50 values <4.5 μg/mL. The tyrosine kinase Epidermal Growth Factor Receptor (EGFR) inhibition studies revealed that compound 12g showed almost similar potency (IC 50 = 0.47 μM) with the Erlotinib (IC 50 = 0.41μM). Molecular docking studies revealed that compounds 12a, 12c and 12g showed encouraging binding energies and inhibition constants on EGFR (PDB ID-4HJO) than the Erlotinib. Finally, the most potent compound 12g was characterized by density functional theory (DFT) with B3LYP/6–311++ G (d, p) basis set. The structural parameters were obtained from geometry optimization. Molecular electrostatic potential (MEP) and highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap and Mulliken atomic charges were calculated. [Display omitted] [ABSTRACT FROM AUTHOR]