Abstract
Background: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. Objective: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. Methods: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. Results: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). Conclusion: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 mu M, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 +/- 0.015 mu M), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 +/- 0.002 mu M. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.