The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the “click-tail” approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with K_is in the range of 50.8–966.8 nM, while the glaucoma associated hCA II was inhibited with K_is in the range of 6.5–760.0 nM. Isoform hCA IV was inhibited with K_is in the range of 65.3–957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with K_is in the range of 30.8–815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.

A series of novel 8-substituted-N-(4-sulfamoylphenyl)quinoline-2-carboxamides was synthesised by the reaction of 8-hydroxy-N-(4-sulfamoylphenyl) quinoline-2-carboxamide with alkyl and benzyl halides. The compounds were assayed for carbonic anhydrase (CA) inhibitory activity against four hCA isoforms, hCA I, hCA II, hCA IV, and hCA IX. Barring hCA IX, all the isoforms were inhibited from low to high nanomolar range. hCA I was inhibited in the range of 61.9–8126 nM, with compound 5h having an inhibition constant of K_I = 61.9 nM. hCA II was inhibited in the range of 33.0–8759 nM, with compound 5h having an inhibition constant of 33.0 nM and compounds 5a and 5b having inhibition constants of 88.4 and 85.7 nM, respectively. hCA IV was inhibited in the range of 657.2–6757 nM. Hence, compound 5h, possessing low nanomolar hCA I and II inhibition, can be selected as a lead for the design of novel CA I and II inhibitors. Graphical Abstract

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.