Optimization of heterocyclic substituted benzenesulfonamides as novel carbonic anhydrase IX inhibitors and their structure activity relationship

In this study, starting from a lead compound discovered by virtual screening, a series of novel heterocyclic substituted benzenesulfonamides were designed and synthesized as new carbonic anhydrase IX (CA IX) inhibitors. Some compounds exhibited potent inhibitory effects against CA IX (in the low nanomolar range) as well as high selectivity against other carbonic anhydrase isozymes (CA I and CA II). The most potent and selective compound 27 could inhibit CA IX in the subnanomolar level with IC50 of 0.48 nM, which increased the potency by about 40-fold against CA IX compared with the lead compound 26, and presented more than 103 fold selectivity over CA I and CA II. The structure–activity relationship (SAR) based on the docking experiments further elucidated the effects of the compounds on the bioactivity and selectivity.

Graphical abstractThrough structural optimization, a more potent and high selectivity CA IX inhibitor 27 was obtained.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Novel benzenesulfonamides CA IX inhibitors were designed and synthesized. ► Structure optimization was carried out on the basis of the lead compound. ► High activity and selectivity of compound 27 was studied and explained.