New Anthranilic Acid Hydrazones as Fenamate Isosteres: Synthesis, Characterization, Molecular Docking, Dynamics & in Silico ADME, in Vitro Anti-Inflammatory and Anticancer Activity Studies.

ABSTRACT

In this study, twenty new anthranilic acid hydrazones 6-9 (a-e) were synthesized and their structures were characterized by Fourier-transform Infrared (FT-IR), Nuclear Magnetic Resonance (1 H-NMR - 13 C-NMR), and High-resolution Mass Spectroscopy (HR-MS). The inhibitory effects of the compounds against COX-II were evaluated. IC50 values of the compounds were found in the range of >200-0.32 µM and compounds 6e, 8d, 8e, 9b, 9c, and 9e were determined to be the most effective inhibitors. Cytotoxic effects of the most potent compounds were investigated against human hepatoblastoma (Hep-G2) and human healthy embryonic kidney (Hek-293) cell lines. Doxorubicin (IC50 8.68±0.16 µM for Hep-G2, 55.29±0.56 µM for Hek-293) was used as standard. 8e is the most active compound, with low IC50 against Hep-G2 (4.80±0.04 µM), high against Hek-293 (159.30±3.12), and high selectivity (33.15). Finally, molecular docking and dynamics studies were performed to understand ligand-protein interactions between the most potent compounds and COX II, Epidermal Growth Factor Receptor (EGFR), and Transforming Growth Factor beta II (TGF-ßII). The docking scores were calculated in the range of -10.609--6.705 kcal/mol for COX-II, -8.652--7.743 kcal/mol for EGFR, and -10.708--8.596 kcal/mol for TGF-ßII.