Synthesis, characterization, molecular docking, in silico ADME study, and in vitro cytotoxicity evaluation of new pyridine derivatives of nabumetone.

Abstract

New pyridine derivatives of nabumetone containing 2-amino 3-cyano moieties were synthesized and aimed to introduce new EGFR kinase inhibitors through two methods either by synthesis of chalcone derivatives initially (1a-d) followed by reacting it with malononitrile and ammonium acetate to form (2a-d) or from a one-pot synthesis of all reactants together to synthesis compounds (2a-e). Melting point, and FT-IR spectra were used to characterize all the synthesized compounds and were confirmed by 1H-NMR, and 13C-NMR spectroscopy. The final compounds (2a-e) were investigated in vitro against A549 (lung cancer cell line) and WRL68 (human normal cell line). compounds (2a, 2b, and 2e) produced marked cytotoxic activity with IC50 (24.62, 23.43, and 24.06 μg/ml) respectively, higher than what obtained from erlotinib with IC50 (25 μg/ml) as a reference drug. Measuring the selectivity index (SI) reveals that all the compounds have high selectivity especially compound (2a) being the most selective towards cancerous cells rather than normal cells with SI two folds higher than erlotinib. The molecular docking study reveals good binding to the EGFR kinase that has a good correlation to the MTT Assay results. In silico ADME study exposes that this synthesized series not only have interesting activity but also shows promised pharmacokinetic properties.

Keywords

• Nabumetone, EGFR inhibitor, cyanopyridine, anticancer, molecular docking