Intramolecular hydrogen bonds of two Teriflunomide analogues

Leflunomide [N-{(4 -trifluoromethyl)phenyl}-5-methylisoxazole-4-carboxamide] is one of the anti-inflammatory, anticancer, and antirheumatic drug.This therapeutic compound is transformed into its active metabolite, Teriflunomide [2- cyano-3-oxo-N-{(4 -trifluoromethyl)phenyl}-2-butenamide] through isoxazole ring opening of Leflunomide. This metabolite is responsible for the biological activity of Leflunomide. In the present study, the structure and intramolecular hydrogen bonds of two active metabolites of leflunomide were inspected by density functional theory calculation at B3LYP/6-311++G** level of theory. The structure of the mentioned compounds was reported by X- ray crystallographic data in the literature. Topological parameters including Electronic charge density (ρ) and its Laplacian (∇2ρ) at critical points of hydrogen bonds are computed for estimating the nature and the strength of intramolecular hydrogen bonds by QTAIM analysis. The hydrogen bond strength, natural charge distribution, steric effects, and electron delocalization were studied using NBO analysis. H-NMR chemical shifts of the hydrogen atoms in the hydrogen bond bridges were computed by GIAO method at the mentioned level of theory.

Keywords:

Leflunomide , Teriflunomide , Hydrogen Bond , DFT , H-NMR , AIM , NBO