Quantum-chemical and physico-chemical properties of hydrochlorothiazide.

The electronic states of hydrochlorothiazide and its related molecules were obtained by CNDO/2 (CNDO = complete neglect of differential overlap), and van der Waals volume and hydrophobic parameters of the substituent of the 6th position in the benzothiadiazine were estimated. The results were discussed from the viewpoint of the structure-activity relationship analysis. Rather lower LUMO (lowest unoccupied molecular orbital level) of hydrochlorothiazide which had been predicted by the iterated Hückel's Molecular Orbital Method was confirmed by CNDO/2 calculation. The introduction of the sulfamoyl group to the 7th position in the benzothiadiazine ring brought out a negative formal charge for the 7th position. The diuretic effect of the substituent of the 6th position in the benzothiadiazine ring was analysed with respect to its van der Waals volume and its hydrophobic parameter. Van der Waals volume seemed to have a close relationship to diuretic activity. The highest correlated coefficient of the regression equation for the structure-activity relationship was obtained using the formal charge of the 7th position in the benzothiadiazine ring, van der Waals volume and the hydrophobic parameter of the substituent of the 6th position. On the basis of result obtained, the model for the action site of hydrochlorothiazide was proposed, consisting of a rather larger, lipophilic hole and an electrostatic interaction site in the tubular membrane.