Sulfocoumarin-, Coumarin-, 4-Sulfamoylphenyl-Bearing Indazole-3-carboxamide Hybrids: Synthesis and Selective Inhibition of Tumor-Associated Carbonic Anhydrase Isozymes IX and XII

A series of sulfocoumarin-, coumarin-, and 4-sulfamoylphenyl-bearing indazole-3-carboxamide hybrids were synthesized and investigated as inhibitors of the human carbonic anhydrase (hCA, EC4.2.1.1) isoformsI and II (cytosolic isozymes), as well as hCAIX and XII (transmembrane, tumor-associated enzymes). Compounds 6a-g (amide derivatives) and 7a-h (triazoles) act as "prodrugs", and their hydrolysis products are the defacto CA inhibitors. These compounds displayed sub-micromolar to high-nanomolar inhibitory activity against hCA isoforms IX and XII, which were recently validated as antitumor drug targets. Moreover, no inhibition of the off-target hCAI and II isoforms was observed. Compounds 8a-f (another set of triazoles) exhibited nanomolar inhibition against hCA isoformsI, II, IX and XII, among which compounds 8c, 8d, and 8f were found to inhibit the tumor-associated hypoxia-induced hCA isoformIX with K-i values of 1.8, 2.3, and 2.0 nm respectively. Further exploration of these compounds could be useful for the development of novel antitumor agents with selective mechanisms of CA inhibitory action.