Investigation of the carbonic anhydrase inhibitory activity of benzenesulfonamides incorporating substituted fused-pyrimidine tails.

Two new series of 2-thiocyclopenta[d]pyrimidine-benzenesulfonamides 12a-l and 2-thiotetrahydroquinazoline-benzenesulfonamides 13a-j were synthesized and evaluated for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory acivity and cytotoxic activity. The derivatives 12a and 12i exerted effective inhibition against CA II with K  = 0.11 and 0.15 µM, while 12a, 12e, 12i, and 13d (K  = 0.083-0.087 µM) were found to be the most potent against CA XII. In addition, higher selectivity toward CA II and CA XII over CA I and CA IX was observed for the majority of the synthesized conjugates. Analysis of the effect of the synthesized compounds on NCI cancer cell lines revealed that compounds 12b and 13d showed mean growth inhibitory effects of 53.59% and 49.25%, respectively. Docking of the synthesized hybrids in the CA II and CA XII binding pockets displayed the capability of the benzenesulfonamide derivatives to form, through their SO NH moiety, the characteristic interactions of the traditional CA inhibitors, besides additional interactions achieved by the tail with isoform-specific residues in the peripheral part of the CA binding sites.