STUDIES OF CARBONIC-ANHYDRASE INHIBITORS - PHYSICOCHEMICAL PROPERTIESAND BIOACTIVITIES OF NEW THIADIAZOLE DERIVATIVES

A series of thiadiazole derivatives of carbonic anhydrase inhibitors w ere prepared and their physicochemical properties and pharmacological activities such as corneal permeabilities, inhibition of carbonic anhy drase activities were evaluated. The solubilities and pKa values were determined in varied pH of phosphate buffers at 35-degrees-C after equ ilibrium. 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) a nd pi (hydrophobic substituent constant) values of substituents were f ound to be correlated to the logarithm of Ka and partition coefficient . Corneal permeabilities of the analogue were determined in a speciall y designed diffusion cell using excised rabbit cornea, which ranged fr om 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 activit y of the analogue. The IC50 values of the analogue around 10(-8) M as determined were less than that of acetazolamide. The results suggest t hat the anaolgue had good pharmacological activity. Finally, an equati on for quantitative structure-activity relationship was established fo r the analogue, which is as follows: log 1/IC50=0.16 pi2 - 0.38sigma 0.16I2 +0.043(logDC)2+7.78 n=9 r=0.994.