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_is 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.