DFT-Based Evaluation of the Drug Dibazol as a Promising Molecular Scaffold Considering Charge State and Solvation Effects

Abstract

Despite considerable research devoted to the synthesis and biological activity of benzimidazole derivatives, their reactivity as molecular systems remains poorly understood. In particular, for dibazol, one of the best-known representatives of this class, the literature has primarily focused on its pharmacological properties and synthetic approaches, while a systematic analysis of its electronic structure and reactivity is virtually absent. Therefore, the present work aims at a quantum-chemical evaluation of the reactivity of dibazol in the neutral and anionic states, taking into account the influence of the environment, as well as the identification of the key reactive centers of the molecule. The scientific significance of the study lies in the systematic analysis of the influence of anionization and solvation on the electronic and thermodynamic characteristics of dibazol, while the practical significance is associated with the possibility of using the obtained data for the targeted synthesis of its derivatives. The calculations were performed using density functional theory (DFT) at the B3LYP/6-311+G(d,p) level with the SMD solvation model. The results show that the anionic form of dibazol is thermodynamically unstable in the gas phase but is stabilized in a polar medium. Analysis of reactivity descriptors and Fukui functions revealed that the C7, C17, and C21 atoms are the main electrophilic sites susceptible to nucleophilic attack, whereas the C15 and C20 atoms exhibit the most pronounced nucleophilic character. The NH group shows comparatively low reactivity. The obtained results contribute to the application of conceptual DFT to the analysis of heterocyclic compounds and can be used in the rational design of new dibazol derivatives with the pre-set properties.