Synthesis, docking studies, in silico ADMET predictions, DFT calculations, and photophysical properties of thiazole-anthracene hybrids as potent EGFR inhibitors

Abstract

The thiazole ring closure of thiosemicarbazones with α-bromo-4-substituted acetophenones was carried out to generate aminothiazole analogues (A1–A16). Experimental methods were used to characterize the developed compounds, including HRMS, 1H, 13C NMR, and elemental analysis. Single-crystal XRD investigations have verified the compound A5 crystal structure. All the synthesized hybrid compounds underwent screening for their anticancer activity against various cancer cell lines, encompassing human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549), as well as normal human breast cell (MCF-10A). The compounds A2, A5, and A8 exhibited excellent anticancer activity against MCF-7 and A549 cancer cell lines compared to the reference drug Erlotinib. Later, in vitro, EGFR results revealed that compared to the reference drug Erlotinib (IC50 value = 0.42 ± 0.04 µM), compounds A2, A5 and A8 displayed the highest tyrosine kinase EGFR inhibitory potency with IC50 values of 1.38 ± 0.11 µM, 0.88 ± 0.05 µM and 1.86 ± 0.12 µM, respectively.Furthermore, in silico molecular docking studies on EGFR (PDB ID: 4HJ0) protein revealed that the potent ligands exhibited higher affinity with an active pocket of receptors showing strong hydrogen bond interactions. The compounds' electronic behaviour, stable geometries, MEP surfaces, and FMO analysis were investigated employing density functional theory (DFT) at the B3LYP level with a 6-311G(d, p) basic set. An in silico ADMET study was also performed to predict the pharmacokinetic and toxicity profile of synthesized compounds, which expressed good oral drug-like behaviour and non-toxic nature. Further, the photophysical properties (UV and fluorescence) of the compounds were discussed.