Small Molecule Alkoxy Oriented Selectiveness on Human Carbonic Anhydrase II and IX Inhibition

We report aryl sulfonamide inhibitors of human carbonic anhydrase (hCA; EC 4.2.1.1) enzymes containing short ureido alkoxy tails. The inhibition potency of such compounds was investigated in vitro on the major hCA isoforms (i.e. I, II, IX, and XII). A selection of the most potent inhibitory derivatives against the hCA IX isoform (i.e. 5a, 5c, and 6c) was studied, and their binding modes on either hCA II and IX-mimic isoform were assessed by X-ray crystallography on the corresponding ligand/protein adducts. This study adds to the field of developing hCA inhibitors at molecular level the critical interactions governing ligand selectivity.

Automated summary

This study reports on the aryl sulfonamide inhibitors of human carbonic anhydrase enzymes and their inhibitory potency against different isoforms. Through X-ray crystallography analysis, the study reveals the critical interactions between the inhibitors and different isoforms. This research has implications for developing highly selective hCA inhibitors.