Computational Chemistry, Hydroxyphenyl Pyruvate Dioxygenase Inhibitor

The thesis is about theoretical calculation on 4-hydroxyphenylpyruvate dioxygenase (HPPD). There are two main parts:In the first part, geometry optimizations were performed at HF/6-31G* level for all of the possible tautomers of benzoylhexanedione. Further calculations were then carried out at different level as for one triketone and two cis-endocyclic double bond enol tautomers, which have relative low energy. We investigated the effect of calculation method and the size of the basis set on the relative stability of the tautomers. The hydrogen bond was described by rotational energy of the hydroxyl hydrogen atom and hereby interpreted the stability of the tautomers. Local hydrogen bonding population analysis was applied to the two enols with lowest energies. With this understanding, the enol-enol tautomeric equilibrium constants and the energy barrier of the benzoylhexane-1, 3-dione were calculated. The solvent effect was fully considered when calculating the equilibrium constants and the results were analyzed by comparing with the experimental results. Finally, calculations were performed on typical 2-substituting benzoylhexane-1, 3-dione derivatives. It appears that the tautomerism free energy and their HPPD inhibitive activity correlated closely.On the other hand, two kinds of keto-enol tautomerism equilibrium were studied. Both the keto-endo and keto-exo equilibrium tend to the latters, which is in good agreement with the experimental observation.The effect of the substituents on the geometries of the benzoxylcyclohexane-1,3-diones. When substituted by nitro group, the conformation of the benzene ring altered because of the steric effect. This favors to the interaction between the Pai-electrons of the benzene ring and the carbonyl group situated to theα-position of it. Thus it is supposed that the specific conformation of the benzene ring results in good binding with the receptor and hereby the high biological activity. Further study on 2,4-disubstituted derivatives shows some regularity between the activities and the conformation of benzene ring. For 2-nitro substituted derivatives, the dihedral angle between the benzene and the plane formed through intramolecular hydrogen bond is usually close to 90°. These compounds also have high activities. Thus our previous presumption was justified.The ion form of the benzoylcyclohexane-1, 3-dione was considered thereafter. The enol tautomers of triketone system can be viewed as vinylogous benzoic acids. For all its possible tautomers, their geometries were optimized at HF/6-31G* level. The two tautomers with lowest energies were then calculated at higher levels. It was found that solvation effect is critical for determining the optimal conformation. The tautomerism and equilibrium constant were calculated between these two ion tautomers.Finally, we calculated the pKa of benzoylcyclohexane-1,3-dione and its derivatives with ab initio methods. On the other hand, pKa was represented by with quantum chemical descriptors such as the charge of the oxygen atom and hydrogen atom as well as the energy of the highest occupied orbit. Good correlations were found thereafter.In the second part, the focus is the quantitative structure-activity relationship (QSAR)...