Razi University

Tautomerism is one of the fundamental concepts in organic chemistry and pharmaceutical sciences, exerting a significant influence on the stability, biological activity, and pharmacological behavior of drugs. This phenomenon can alter various pharmacokinetic and pharmacodynamic properties such as absorption, metabolism, toxicity, and blood–brain barrier permeability. Moreover, cytochrome P450 enzymes, as the primary systems involved in drug metabolism, play a crucial role in the oxidation and structural transformation of pharmaceutical compounds In this study, the tautomeric behavior and structural properties of two drug compounds, Guanabenz and its oxime derivative Guanoxabenz, were investigated using computational chemistry methods. The main objective of this research was to understand the relative stability, equilibrium tendency, and environmental effects on the tautomeric balance of these compounds. Initially, all possible tautomeric structures of Guanabenz and Guanoxabenz were theoretically designed and optimized. Subsequently, Density Functional Theory (DFT) calculations were performed at the B3LYP/6-31G* level to determine the minimum energy structures and evaluate thermodynamic parameters such as Gi   free energy and dipole moment. In the next step, the molecular docking of Guanabenz and its oxidation pathway were analyzed. Quantum chemical results revealed that among the four tautomers of Guanabenz, the G4 structure exhibited the highest polarity and hydrophilicity, while G1, with the lowest dipole moment, showed the greatest hydrophobicity and consequently higher thermodynamic stability under biological conditions. The equilibrium analysis indicated that although G4 is relatively more stable, G1 is the most thermodynamically favored form in biological environments. Docking studies demonstrated that G3 exhibited the strongest interaction with the ??-adrenergic receptor, indicating that it is the most active tautomer in terms of drug–receptor binding. These findings provided a clear understanding of the structural and functional behavior of Guanabenz tautomers in different media. Furthermore, the computational analysis of Guanabenz’s oxime derivative, Guanoxabenz, showed that the GO1 tautomer is the most stable structure among the others, except in the gas phase, where GO3trans exhibits the highest stability. In terms of polarity, GO2, with a dipole moment of 5.09 Debye in aqueous medium, was identified as the most hydrophilic tautomer, while GO1, with a dipole moment of 3.20 Debye, was the most hydrophobic. In addition, the reaction pathway analysis indicated that during the oxidation process of Guanabenz, the direct N-oxidation accompanied by proton transfer is the most probable mechanism compared to the hydrogen abstraction pathway. Overall, the findings of this research demonstrate that tautomerism and its related electronic characteristics play a crucial role in determining the stability, polarity, and biological behavior of Guanabenz and Guanoxabenz, and these insights can be effectively applied to the rational design of new derivatives with improved stability and pharmacological properties.