Synthesis of human carbonic anhydrase inhibitors with structure of 4-substituted pyridine-3-sulfonamide

In recent years, several new molecular targets for anti-cancer therapy have been identified. Among them the isoform IX of human carbonic anhydrase (hCAIX) has been shown to be strongly associated with hypoxic tumors. In several previous publications, we have shown high inhibition level against hCAIX for several series of pyridine-3-sulfonamide derivatives. Thus this research, in order to enhance inhibition properties and obtain compounds with high selectivity, we have synthesized a series of novel compounds containing the 1,2,3-triazole substituent in the position 4 of the pyridine-3-sulfonamide scaffold, based on our previous results which showed that aromatic substituents in position 4 are favored for the activity. The synthesis of these compounds was based on the mechanism of copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) “click” reaction. The structure of the new compounds was confirmed using the spectroscopic methods: IR, ¹H NMR, and elemental analysis (C, H, N). The in vitro antitumor activity study was performed with the MTT assay against 3 human tumor cell lines (MCF-7, HCT-116 and HeLa). Based on the computational methods, the ADME parameters were determined and the interactions of the obtained compounds with the active site of the hCAIX and hCAII enzymes were simulated. The vast majority of the new compounds show a higher affinity for cancer associated hCAIX than for ubiquitous isoform hCAII.