Quantum Chemical Studies On Solvent Effects And Their Applications In Drug Design

Quantum-chemical descriptors have been widely applied to structure-activity relationship studies in biochemistry or pharmaceutical chemistry. These descriptors are usually acquired by quantum chemical calculations in vacuum, however, all biochemical process refer to liquid media. Such contradiction intrigues us to investigate the solvent effects of molecular systems by quantum chemical methods. The main results in present article fall into three parts and can be summarized as follows.In the first part, the prototropic hydroxy-oxo tautomerisms of 2(1H)-pyridones/2-hydorxypyridines, one of the most important model systems in molecular biology, have been investigated with self-consistent reaction field method based on continuum model. The influence of the nature and position of substituent groups, the existence of intramolecular hydrogen bonding and tautomeric competition between 2-hydroxy and 4-hydroxy on the tautomeric equilibria have also been examined. The results obtained form theoretical calculations indicate that the hydroxyl- tautomer predominate in the gas phase or nonpolar solvents, while in solvents of high dielectric constant, the tautomeric equilibria is shift in favor of the oxo- tautomer can be mainly ascribed to the polarization effects. It is noticeable that the changes of polarity of two tautomers that caused by the substituent groups, beside the total energies of the derivative compounds themselves, must be taken into account in examining the influences of substituent groups on the tautomeric equilibria.Other isomeric systems which be sensitive to the nature of solvents, including the tautomerisms of 2(1H)-pyridazinone and its derivatives, tetramic acids, imidazole-1-ylacetic acid, and the Z-E isomerism of enaminones have further been examined. According to the results obtained form the studies on above systems, we point out that it is reasonable to investigate the solvent effects with SCRF approach on those systems contained heterocycles which the polarization effects is dominant, but for the chain molecule, it deserve careful consideration.Quantum chemical calculations account for solvent effects have been performed for two bipyridine cardiotonic drugs and several model quinolone molecules, two piece of viewpoint have been elucidated. (1) Beside the factor of conformation, the...