A theoretical study of a family of 2-benzyl-3-methylquinoxaline 1,4-di-n-oxide derivatives

E. VICENTE; P. R. DUCHOWICZ; M. G. VITALE; S. PEREZ-SILANES; I. ALDANA; E. A. CASTRO; R. PIS DIEZ; A. MONGE

Bruselas

Simposio; XXI International Symposium on Medicinal Chemistry; 2010

The quinoxaline derivatives are a class of compounds that show very interesting biological properties (antibacterial, antiviral, anticancer, antifungal, antihelmintic, and insecticidal). The oxidation of both nitrogens of this heterocyclic system, needed for obtaining quinoxaline 1,4-di-N-oxide derivatives, greatly increases the number of biological properties [1]. In fact, recent studies have demonstrated that quinoxaline 1,4-di-N-oxides are endowed with antimycobacterial, antiprotozoal, and anticandida activities as well as mutagenic properties, depending on specific chemical features [1]. In our continuing efforts to find new compounds with therapeutical activities, a series of 2-benzyl-3-methylquinoxaline 1,4-di-N-oxide derivatives was proposed, synthesized and published [2]. This work recorded the IR and 1H-NMR spectra of the new species as part of their characterization studies, but no reference to structural parameters was given. In order to further describe the chemistry of aforementioned compounds, hybrid density functional calculations were performed on them, following a similar methodology as previously described [3]. The conformational space of each one of the ten 2-benzyl-3-methylquinoxaline 1,4-di-N-oxide derivatives analyzed was scanned using a classical molecular dynamics module of the HyperChem package for the simulation (MM+ Molecular Mechanics Force Field). The 40 lowest-energy molecular conformations of each molecule obtained showed total energies that were mostly grouped, as evidenced by their flat (quinoxaline) structures. These conformations were subjected to further geometry optimization in Gaussian03 program using the density functional theory of B3LYP/6-31G(d,p), and in this way, the most stable conformation resulting from each derivative is selected. The harmonic vibrational frequencies were calculated using the same level of theory. In addition, the isotropic chemical shifts for hydrogen atoms were also calculated, with the isotropic magnetic shielding tensor obtained at the B3LYP/6-311+G(2d,p) level. In brief, optimized geometries, harmonic vibrational frequencies, and 1H chemical shifts were reported and compared with experimental data when available. The systematic-theoretical study carried out enabled us to obtain geometric data in quinoxaline 1,4-di-N-oxide derivatives that did not pose experimental values, and suggested the preferential conformations that these biological systems would adopt during their interaction with the substrate.