Synthesis, characterization, and in silico modelling of chrysin derivatives and their transition metal (II) complexes as potential androgen receptor antagonists for prostate cancer therapy

Abstract

Chrysin, a flavonoid has been derivatised through benzoylation and the use of phenylhydrazine to give 7-ortho-benzoyl chrysin (GA) and 2-pheny-4-(2-phenylhydrozono)-4H-chromene-5,7-diol (ZH) derivatives. Metal(II) complexes of GA and ZH derivatives have been synthesized and characterized by percentage metal analysis, infrared and electronic spectroscopies, magnetic susceptibility and melting points. The In-silico studies of GA, ZH and their complexes were conducted against prostate cancer androgen receptor (PDB id 1e3g) using Python Prescription (PyRx) and visualized using Biovia Discovery 2024 with Abiraterone acetate as standard drug. The ADMET (Adsorption, Distribution, Metabolism, Excretion and Toxicity) analysis of the synthesized compounds and the standard drug was carried out using SwissADME and (Prediction of Toxicity of Chemicals) Protox 3.0. From the Infrared spectra data GA and ZH behave as bidentate ligands with GA coordinating to the metals through the carbonyl oxygen of the chromone group (1740 -1742cm^-1) and the phenolic oxygen of the hydroxyl moiety (3169- 3074cm^-1) at position seven, while ZH bonded through the imine nitrogen (1632-633cm^-1) and the phenolic hydroxyl oxygen (3058-3062cm^-1). The magnetic susceptibility and electronic spectral data indicated that the metal (II) complexes have octahedral geometries. The docking results showed that GA, [Cu(GA)₂(H₂O)₂].2 H₂O, [Ni(GA)₂(H₂O)₂], [Co(GA)₂(H₂O)₂]. H₂O with docking score values of -9.3 kcal/mol, -9.4 kcal/mol, -10.0 kcal/mol and -10.5 kcal/mol interact more with amino acids in the active sites of receptor protein androgen via H-bond, pi-pi interaction than the standard drugs Abiraterone acetate (docking score -8.8.0 kcal/mol). ADMET analysis showed good oral bioavailability of GA and [Co(GA)₂(H₂O)₂]. H₂O among the complexes, less toxicity but low gastrointestinal absorption of [Co(GA)₂(H₂O)₂]. H₂O compared to Abiraterone acetate which might limit its potential as a lead as anti-androgen drug against prostate cancer.