Studies of carbonic anhydrase inhibitors: physicochemical properties and bioactivities of new thiadiazole derivatives.

Abstract

A series of thiadiazole derivatives of carbonic anhydrase inhibitors were prepared and their physicochemical properties and pharmacological activities such as corneal permeabilities, inhibition of carbonic anhydrase activities were evaluated. The solubilities and pKa values were determined in varied pH of phosphate buffers at 35 degrees C after equilibrium. Intrinsic solubility and pKa value were calculated from the plot of solubility versus the reciprocal of hydrogen ion concentration. The distribution coefficient was determined in the system of octanol/pH 7.65 phosphate buffer. As a result, the sigma (Hammett constant) and pi (hydrophobic substituent constant) values of substituents were found to be correlated to the logarithm of Ka and partition coefficient. Corneal permeabilities of the analogue were determined in a specially designed diffusion cell using excised rabbit cornea, which ranged from 1.32 x 10(-5) (compound II) to 3.48 x 10(-7) cm/sec (compound VI). Compound with high permeability might be expected to be absorbed well after topical administration into the eye. The methodology of pH-stat was used to determine the inhibition of the carbonic anhydrase activity of the analogue. The IC50 values of the analogue around 10(-8) M as determined were less than that of acetazolamide. The results suggest that the analogue had good pharmacological activity. Finally, an equation for quantitative structure-activity relationship was established for the analogue, which is as follows: [formula: see text]