Synthesis, Characterization, in silico DFT, Molecular docking, ADMET Profiling Studies and Toxicity Predictions of Ag(I) Complex Derived from 4-Aminoacetophenone

The reaction of the synthesized (E)-1-(4-((2,4-dihydroxy-6-methylphenyl)diazenyl)phenyl)ethan-1-one, (DMPDE) ligand with Ag(I) ion at room temperature resulted in the formation of the complex; [Ag(DMPDE)(H2O)2]. 1H NMR, 13C NMR, FTIR, UV-Vis, mass spectra, elemental analyses, thermal analysis (TGA/DTA), and molar conductance measurements were done to elucidate the structure of synthetic compounds. The results revealed an interesting geometrical variation; tetrahedral for Ag(I) complex. FT-IR spectra demonstrated that the ligand (DMPDE) under investigation behaves as a bidentate ligand (N,O) through the nitrogen atom of the azo group which is the farthest of the acetophenone moiety and oxygen phenolic for benzene moiety and forms a stable five-membered chelating ring. The electronic structure, molecular electrostatic potential (MEP) and quantum chemical calculations of the newly synthesized compounds are investigated theoretically at the DFT/B3LYP level of theory. Additionally, the ligand (DMPDE) and Ag(I) complex were screened against the growth of pathogenic bacteria [Actinomycosis (G+), E. Escherichia Coli (G-)] and fungi (Penicillium spp.) compared with the reference antibiotics, Chloramphenicol and Nystatin. Furthermore, 1,1-diphenyl-2-picrylhydrazyl (DPPH) was used to evaluate the antioxidant activities of the ligand and its complex, which showed they both possess significant antioxidant properties in comparison with L-ascorbic acid (Vit. C) as standard. Based on docking studies, (DMPDE) and Ag(I) complex demonstrated a greater affinity for (PDB ID: 3T88), which corresponds to Escherichia coli protein (-6.7818 kcal/mol) and (-6.7928 kcal/mol), respectively. Interestingly, the most active Ag(I) complex inside the active site of cervical cancer receptor (PDB ID: 4XR8) demonstrated a higher binding energy (-6.2631 kcal/mol) than free ligand (-5.8561 kcal/mol). In silico, ADMET displayed that compounds obey the Lipinski rule and the "Veber's rule. Consequently, is likely to exhibit oral bioavailability with good LD50 and a safety profile that includes non-cytotoxicity, non-immunotoxicity, and non-skin sensitization. Finally, the compounds synthesized showed significant anticancer activity in human cervical cancer cell lines HeLa and SiHa compared with positive controls (cisplatin) and normal human hepatic cells (WRL-68). In the present study, all tested cancer cell lines showed promising activity against Ag(I) complex, whose IC50 value ranged from (61.02 to 71.09) mu g/mL. Our groundbreaking research encompasses the first-time synthesis and characterization of DMPDE and its Ag(I)-Complex. Utilizing Density Functional Theory, we calculated crucial theoretical parameters. The synthesized compounds displayed notable antibacterial efficacy against diverse pathogens and exhibited significant antioxidant activity via DPPH radical scavenging. In-depth molecular docking studies elucidated interaction mechanisms, coupled with comprehensive in-silico ADME profiling for bioavailability assessment. In vitro anticancer evaluations against HeLa and SiHa cell lines, compared with cisplatin, demonstrated promising anticancer potential while sparing normal human liver cells (WRL-68). This multifaceted study contributes vital insights into the synthesis, properties, and diverse biological activities of the investigated compounds. image