A novel imidazole-based azo molecule: synthesis, characterization, quantum chemical calculations, molecular docking, molecular dynamics simulations and ADMET properties

Abstract

Context: Today, the treatment or prevention of cancer, which is one of the most important causes of death, has a very important place. On the other hand, the discovery of new antimicrobial agents is also important because of antibiotic resistance that can occur in humans. For these reasons, in this study, the synthesis, quantum chemical calculations, and in silico studies of a novel azo molecule with high bioactive potential were carried out. In the first step of the synthesis part, (3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline compound, which is the raw material of the drug used in cancer treatments, was synthesized. In the second step, a novel product 2-hydroxy-5-((3-(4-methyl-1H-imidazol-1-yl)-5-trifluoromethyl)phenyl)diazenyl)benzaldehyde (HTB) was obtained as a result of the reaction of salicylaldehyde coupling to this compound. Then, as it was being spectroscopically described, its geometry was optimized. In order to perform quantum chemical calculations, the molecular structure, vibrational spectroscopic data, electronic transition absorption wavelengths, HOMO and LUMO analyses, molecular electrostatic potential (MEP) and potential energy surface (PES) of the molecule were all taken into consideration. Using molecular docking simulations, in silico interactions of the HTB molecule with some anticancer and antibacterial-related proteins were studied. In addition, the ADMET parameters of the HTB were also predicted.

Methods: The structure of the synthesized compound was elucidated using ¹H-NMR, ¹³C-NMR (APT), ¹⁹F-NMR, FT-IR and UV-vis spectroscopic methods. The optimized geometry, molecular electrostatic potential diagram and vibrational frequencies of the HTB molecule were calculated at the DFT/B3LYP/6-311G(d,p) level. The TD-DFT method was used to calculate HOMOs-LUMOs and electronic transitions, and the GIAO method was used to calculate chemical shift values. It was observed that the experimental spectral data were in good agreement with the theoretical ones. Molecular docking simulations of the HTB molecule using 4 different proteins were investigated. Two of these proteins were involved in simulating anticancer activity and the other two in simulating antibacterial activity. According to molecular docking studies, the binding energies of the complexes formed by the HTB compound with the 4 selected proteins were between -9.6 and -8.7 kcal/mol. HTB showed the best affinity with VEGFR2 protein (PDB ID: 2XIR) and the binding energy of this interaction was found to be -9.6 kcal/mol. The HTB-2XIR interaction was examined with molecular dynamics simulation for 25 ns and it was determined that this complex was stable during this time. In addition, the ADMET parameters of the HTB were also calculated, and from these values, it was determined that the compound has very low toxicity and high oral bioavailability.

Keywords: ADMET; Anticancer; Density functional theory; Molecular docking; Molecular dynamics.