Design and synthesis of 3-(azepan-1-ylsulfonyl)- <i>N</i> -aryl benzamide derivatives as potent carbonic anhydrase IX inhibitors with anticancer activities

Carbonic anhydrase IX (CAIX) is known to be overexpressed in various tumors and plays a significant role in tumor development and progression. A series of 3-sulfonamide benzoate derivatives with a 7-membered azepane ring were synthesized and evaluated for their CAIX inhibitory activities. Most of the synthesized compounds successfully inhibited CAIX activities, exhibiting IC₅₀ values in the low nanomolar range. The most potent CAIX inhibitor was compound <b>26</b>, with an IC₅₀ of 19 nM. A structure-activity relationship analysis of the synthesized compounds was conducted, and molecular docking revealed strong coordination with the catalytic Zn²⁺ metal, hydrophobic interactions of the azepane ring with a hydrophobic pocket, and π-stacking interactions of the aryl ring with an aromatic surface. The three most active analogues (<b>8</b>, <b>16</b>, and <b>26</b>) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines screen. Notably, compound <b>16</b> (CAIX, IC₅₀ = 310 nM) demonstrated potent growth inhibitory effects against several cancer cell lines.