2-Aminophenol-based ligands and Cu(II) complexes: Synthesis, characterization, X-ray structure, thermal and electrochemical properties, and in vitro biological evaluation, ADMET study and molecular docking simulation

Abstract

Two ligands 2-[(2,4-dimethoxybenzylidene)amino]phenol (HA), 2-[(2,5-dimethoxybenzylidene)amino]phenol (HB) and their Cu2+ transition metal complexes were synthesized and characterized by elemental analysis, mass spectra, UV–vis, 1H and 13C NMR (only used for HA and HB) and FTIR methods. Single crystals of the ligands HA and HB were obtained from ethanol solution, and single-crystal X-ray diffraction techniques have elucidated their molecular structures. Thermal properties of the 2-amino phenol-based ligands (HA and HB) and their Cu2+ metal complexes have been investigated by using thermogravimetric (TGA) and differential thermal analyses (DTA) methods. The electrochemical properties of all compounds have been studied in the -1.1 to +1.1 V range. In vitro antimicrobial activity was screened against two gram-positive (Staphylococcus aureus and Bacillus cereus), two gram-negative (Escherichia coli and S. typhimurium), and one fungal strain (Candida albicans) and compounds exhibited bactericidal and fungicidal behavior. The cytotoxic properties of the compounds were evaluated on HUVEC and MCF-7 cells by calculating IC50 values for both cell types. The smallest IC50 values ​​of the compounds tested were 34.19 µM for the HA compound in the MCF-7 cell line, while they were calculated to be 17.67 µM for the HB compound in the HUVEC cell line. In addition to the wet laboratory investigations, the ADMET characteristics of the compounds were thoroughly assessed, and none of them were found to violate any drug similarity rules. The synthesized compounds' physicochemical and pharmacological characteristics stayed within Lipinski's RO5 projected limits and have a high bioavailability profile according to ADMET data. In silico toxicity studies revealed that the compounds did not show AMES toxicity and hepatotoxicity. In silico, target receptor predictions of the compounds were performed, and their potential to be kinase inhibitors was high. Therefore, BRAF (V600E) protein kinase was selected target protein in molecular docking studies. Molecular docking studies revealed that all compounds exhibited a significant affinity for crucial residues in the enzyme's active site, confirming the inhibitory nature of BRAF (V600E) protein kinase, showing both polar and apolar interactions.