Design, Synthesis, and Biological Evaluation of 1,2,3-Triazole-linked triazino[5,6-b]indole-benzene sulfonamide Conjugates as Potent Carbonic Anhydrase I, II, IX, and XIII Inhibitors

A series of 1,2,3-triazole-linked triazino[5,6-b]indole-benzene sulfonamide hybrids (6a–6o) was synthesized and evaluated for carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity against the human (h) isoforms hCA I, II, XIII (cytosolic isoforms), and hCA IX (transmembrane tumor-associated isoform). The results revealed that the compounds 6a–6o exhibited K(i) values in the low to medium nanomolar range against hCA II and hCA IX (K(i)s ranging from 7.7 nM to 41.3 nM) and higher K(i) values against hCA I and hCA XIII. Compound 6i showed potent inhibition of hCA II (K(i) = 7.7nM), being more effective compared to the standard inhibitor acetazolamide (AAZ) (K(i) = 12.1 nM). Compounds 6b and 6d showed moderate activity against hCA XIII (K(i) = 69.8 and 65.8 nM). Hence, compound 6i could be consider as potential lead candidate for the design of potent and selective hCA II inhibitors.