Quantitative structure–activity relationship analysis of N2,N4-di-tert-butyl-6-chloro-1,3,5-triazine-2,4-diamine derivatives; a DFT study

A number of N-heterocyclic compounds in the aromatic or long carbon chain system have been reported as being effective inhibitors [1]. The remarkable inhibitory effect is reinforced by the presence of heteroatoms such as sulfur (S), oxygen (O) and nitrogen (N) [2]. Density Functional theory (DFT) has been recently used [3], to describe the interaction between the activities and molecular structures. A quantitative structure–activity relationship (QSAR) study is performed on a set of N2,N4-di-tert-butyl-6-chloro-1,3,5-triazine-2,4-diamine derivatives to reveal structural and quantum-chemical features influencing the toxic effect. Because toxicity of N2,N4-di-tert-butyl-6-chloro-1,3,5-triazine-2,4-diamine compounds is dependent on conformational properties, a conformational search has been performed before optimization of geometries. All quantum-chemical calculations are carried out at DFT/B3LYP level of theory with 6-311+G basis set. Frequency calculations are performed after full geometry optimization. The aim of this paper is to study the relationships between the molecular structures of N2,N4-di-tert-butyl-6-chloro-1,3,5-triazine-2,4-diamine. The results indicate that the charge on nitrogen atom plays an important role in the toxic behavior. Electron density, as well as kinetic energy densities influence the toxic effect of N2,N4-di-tert-butyl-6-chloro-1,3,5-triazine-2,4-diamine compounds. Also, higher values of dipole moment indicate the higher toxicity in current compound series. This study shows that the nature of substituents has very important determining role in toxicity of these compounds. Also, it was found that molecular charge distribution and strength of the bonds play vital role in stability of compound, which is directly related to its toxicity. Through the method of quantum chemical calculations, the structural parameters, such as the frontier molecular orbitals (MO), energy gap (ΔEgap), dipole moment (μ), hardness (ŋ), softness (σ) and electrophilicity index (χ) were calculated and correlated using QSAR.