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

Abstract

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 26, 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 (8, 16, and 26) were further tested for their antiproliferative activities in the NCI-60 human tumor cell lines screen. Notably, compound 16 (CAIX, IC₅₀ = 310 nM) demonstrated potent growth inhibitory effects against several cancer cell lines.

Keywords: cancer; carbonic anhydrase; docking; sulfonamide; synthesis.